Introduction: Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. Case Presentation: Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range. Conclusion:THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.

1.
Onigata
K
,
Szinnai
G
.
Resistance to thyroid hormone
.
Endocr Dev
.
2014
;
26
:
118
29
.
2.
Erbas
IM
,
Demir
K
.
The clinical spectrum of resistance to thyroid hormone alpha in children and adults
.
J Clin Res Pediatr Endocrinol
.
2021
;
13
(
1
):
1
14
.
3.
Bochukova
E
,
Schoenmakers
N
,
Agostini
M
,
Schoenmakers
E
,
Rajanayagam
O
,
Keogh
JM
, et al
.
A mutation in the thyroid hormone receptor alpha gene
.
N Engl J Med
.
2012
;
366
(
3
):
243
9
.
4.
van Mullem
A
,
van Heerebeek
R
,
Chrysis
D
,
Visser
E
,
Medici
M
,
Andrikoula
M
, et al
.
Clinical phenotype and mutant TRα1
.
N Engl J Med
.
2012
;
366
(
15
):
1451
3
.
5.
Tylki-Szymanska
A
,
Acuna-Hidalgo
R
,
Krajewska-Walasek
M
,
Lecka-Ambroziak
A
,
Steehouwer
M
,
Gilissen
C
, et al
.
Thyroid hormone resistance syndrome due to mutations in the Thyroid Hormone Receptor α gene (THRA)
.
J Med Genet
.
2015
;
52
(
5
):
312
6
.
6.
van Gucht
AL
,
Meima
ME
,
Zwaveling-Soonawala
N
,
Visser
WE
,
Fliers
E
,
Wennink
JMB
, et al
.
Resistance to thyroid hormone alpha in an 18-month-old girl: clinical, therapeutic, and molecular characteristics
.
Thyroid
.
2016
;
26
(
3
):
338
46
.
7.
Demir
K
,
van Gucht
ALM
,
Büyükinan
M
,
Çatlı
G
,
Ayhan
Y
,
Baş
VN
, et al
.
Diverse genotypes and phenotypes of three novel thyroid hormone receptor-α mutations
.
J Clin Endocrinol Metab
.
2016
;
101
(
8
):
2945
54
.
8.
Moran
C
,
Agostini
M
,
McGowan
A
,
Schoenmakers
E
,
Fairall
L
,
Lyons
G
, et al
.
Contrasting phenotypes in resistance to thyroid hormone alpha correlate with divergent properties of thyroid hormone receptor α1 mutant proteins
.
Thyroid
.
2017
;
27
(
7
):
973
82
.
9.
Sun
H
,
Wu
H
,
Xie
R
,
Wang
F
,
Chen
T
,
Chen
X
, et al
.
New case of Thyroid Hormone Resistance α caused by a mutation of THRA/TRα1
.
J Endocr Soc
.
2019
;
3
(
3
):
665
9
.
10.
Korkmaz
O
,
Ozen
S
,
Ozdemir
TR
,
Goksen
D
,
Darcan
S
.
A novel thyroid hormone receptor alpha gene mutation, clinic characteristics, and follow-up findings in a patient with thyroid hormone resistance
.
Hormones
.
2019
;
18
(
2
):
223
7
.
11.
Freire
BL
,
Homma
TK
,
Funari
MFA
,
Lerario
AM
,
Vasques
GA
,
Malaquias
AC
, et al
.
Multigene sequencing analysis of children born small for gestational age with isolated short stature
.
J Clin Endocrinol Metab
.
2019
;
104
(
6
):
2023
30
.
12.
Pejaver
V
,
Byrne
AB
,
Feng
BJ
,
Pagel
KA
,
Mooney
SD
,
Karchin
R
, et al
.
Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendations for PP3/BP4 criteria
.
Am J Hum Genet
.
2022
;
109
(
12
):
2163
77
.
13.
Cheng
J
,
Novati
G
,
Pan
J
,
Bycroft
C
,
Žemgulytė
A
,
Applebaum
T
, et al
.
Accurate proteome-wide missense variant effect prediction with AlphaMissense
.
Science
.
2023
;
381
(
6664
):
eadg7492
.
14.
Richards
S
,
Aziz
N
,
Bale
S
,
Bick
D
,
Das
S
,
Gastier-Foster
J
, et al
.
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology
.
Genet Med
.
2015
;
17
(
5
):
405
24
.
15.
Refetoff
S
,
Weiss
RE
,
Usala
SJ
.
The syndromes of resistance to thyroid hormone
.
Endocr Rev
.
1993
;
14
(
3
):
348
99
.
16.
Refetoff
S
,
Bassett
JHD
,
Beck-Peccoz
P
,
Bernal
J
,
Brent
G
,
Chatterjee
K
, et al
.
Classification and proposed nomenclature for inherited defects of thyroid hormone action, cell transport, and metabolism
.
Eur Thyroid J
.
2014
;
3
(
1
):
7
9
.
17.
Dahll
LK
,
Westbye
AB
,
Vinorum
K
,
Sejersted
Y
,
Barøy
T
,
Thorsby
PM
, et al
.
Clinical and biochemical characteristics of untreated adult patients with resistance to thyroid hormone alpha
.
J Endocr Soc
.
2023
;
7
(
8
):
bvad089
.
18.
Espiard
S
,
Savagner
F
,
Flamant
F
,
Vlaeminck-Guillem
V
,
Guyot
R
,
Munier
M
, et al
.
A novel mutation in THRA gene associated with an atypical phenotype of resistance to thyroid hormone
.
J Clin Endocrinol Metab
.
2015
;
100
(
8
):
2841
8
.
19.
le Maire
A
,
Bouhours-Nouet
N
,
Soamalala
J
,
Mirebeau-Prunier
D
,
Paloni
M
,
Guee
L
, et al
.
Two novel cases of resistance to thyroid hormone due to THRA mutation
.
Thyroid
.
2020
;
30
(
8
):
1217
21
.
20.
Tang
Y
,
Yu
M
,
Lian
X
.
Resistance to thyroid hormone α, revelation of basic study to clinical consequences
.
J Pediatr Endocrinol Metab
.
2016
;
29
(
5
):
511
22
.
21.
Moran
C
,
Schoenmakers
N
,
Agostini
M
,
Schoenmakers
E
,
Offiah
A
,
Kydd
A
, et al
.
An adult female with resistance to thyroid hormone mediated by defective thyroid hormone receptor α
.
J Clin Endocrinol Metab
.
2013
;
98
(
11
):
4254
61
.
22.
van Gucht
ALM
,
Moran
C
,
Meima
ME
,
Visser
WE
,
Chatterjee
K
,
Visser
TJ
, et al
.
Resistance to thyroid hormone due to heterozygous mutations in thyroid hormone receptor alpha
.
Curr Top Dev Biol
.
2017
;
125
:
337
55
.
23.
Plachy
L
,
Strakova
V
,
Elblova
L
,
Obermannova
B
,
Kolouskova
S
,
Snajderova
M
, et al
.
High prevalence of growth plate gene variants in children with familial short stature treated with GH
.
J Clin Endocrinol Metab
.
2019
;
104
(
10
):
4273
81
.
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