CASE REPORT
Nagoya J. Med. Sci. 85. 369–374, 2023
doi:10.18999/nagjms.85.2.369

Eighteen-years follow-up of congenital hypothyroidism byTSHR gene p.Arg109Gln and p.Arg450His variants
Daisuke Watanabe, Hideaki Yagasaki, Yumiko Mitsui and Takeshi Inukai
Department of Pediatrics, Faculty of Medicine, University of Yamanashi, Chuo, JapanABSTRACT
Congenital hypothyroidism (CH) is a common heterogeneous endocrine disorder. The thyroid-stimulating
hormone receptor gene (TSHR) is one of the major candidate genes associated with CH. Studies haveinvestigated the possible correlations between the specific clinical features and the presence of TSHR variants. However, only a few reports have focused on the long-term follow-up of patients with CH. Here wepresent a case of CH-associated TSHR p.Arg109Gln and p.Arg450His rare compound heterozygous variants,
with a follow-up performed until adolescence. The patient had high serum TSH levels during newborn
screening. Oral administration of levothyroxine (l-T4) was initiated at 1 month of age. The ultrasonogram
revealed normal thyroid morphology and blood flow. Reduced uptake of I-123 and negative perchlorate
test was observed. A small amount of l-T4 remained needed although l-T4 could be steadily reduced bypuberty. The patient was diagnosed with orthotopic, nongoitrous, and permanent CH. He had no nonclassical
TSH resistance. Patients with the TSHR p.Arg109Gln compound heterozygous variant exhibit permanent
CH with high TSH levels and normal or slightly lower fT4 levels. In the future, genotype identification
could help predict the long-term prognosis and reduce the requirement for detailed examinations. Morecase studies are needed to determine the relationship between genetic variants and clinical features in CH.
Keywords: congenital hypothyroidism, TSHR, p.Arg109Gln, genotype-phenotype, nonclassical TSH resistance
Abbreviations:
CH: congenital hypothyroidism
TSHR: thyroid-stimulating hormone receptor genel-T4: levothyroxine
This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 InternationalLicense. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).

INTRODUCTION
Congenital hypothyroidism (CH) is a common heterogeneous endocrine disorder, of whichapproximately 20% of cases are caused by a single gene variant. The thyroid-stimulating hormone
receptor gene (TSHR) variants majorly contribute to the development of nongoitrous CH.1 Several
studies have investigated the phenotypes associated with specific TSHR variants. However, only
a few reports have focused on the long-term follow-up of patients with CH. Thus, determining
Received: April 18, 2022; accepted: June 13, 2022
Corresponding Author: Daisuke Watanabe, MD, PhD
Department of Pediatrics, Faculty of Medicine, University of Yamanashi, 1110 Shimokato, Chuo 409-3898,
Japan
Tel: +81-55-273-9606, Fax: +81-55-273-6745, E-mail: dwatanabe@yamanashi.ac.jp369

Daisuke Watanabe et al

the clinical features of CH in adolescents is difficult. Here, we report a case of CH that isassociated with the TSHR p.Arg109Gln and p.Arg450His compound heterozygous variants, which
was followed-up for 18 years.

CASE REPORTAn 18-year-old Japanese boy patient had a history of CH. He was born full-term at 40 weeks
gestation with a birth weight of 2,818 kg. High serum TSH levels (22.7 µIU/mL) were detectedduring newborn screening although goiter was not observed. Both parents had normal thyroid
function. The thyroid function tests of his father revealed that serum TSH, free T3, and freeT4 levels were 0.196 µIU/mL, 4.44 pg/mL, and 1.59 ng/dL, respectively. Those of his motherwere 1.44 µIU/mL, 3.09 pg/mL, and 1.19 ng/dL, respectively. The initial examination of thyroid
function during detail tests revealed that serum TSH, free T3, free T4, and thyroglobulin levels
were 41 µIU/mL, 4.29 pg/mL, 1.59 ng/dL, and 160 ng/mL, respectively. Oral levothyroxine(l-T4) administration was initiated at 1 month of age, which led to a TSH level reduction. The
distribution of 18-year detailed clinical history, such as dose of l-T4 and serum TSH levels, isshown in Figure 1. The patient received l-T4 in oral doses of 8.37, 8.21, and 6.92 µg/kg/day
at 1, 2, and 3 years of age, respectively. At 7 years of age, the patient underwent a diagnosticreevaluation, which revealed the serum TSH, free T3, free T4, and thyroglobulin levels as 47.59µIU/mL, 3.44 pg/mL, 0.94 ng/dL, and 84.95 ng/mL, respectively. The ultrasonogram revealed
normal thyroid morphology and blood flow, and the thyroid size of the right lobe was 27.3 ×
8.0 × 8.8 mm, the left lobe was 22.1 × 10.3 × 8.3 mm, and the isthmus was 1.4 mm. Reduced
uptake of I-123 (8.5%, 8.7%, and 7.8% at 3, 6, and 24 h, respectively) and negative perchlorate
test were observed. The thyrotropin-releasing hormone stimulation test at 0, 15, 30, 45, 60, 90,
and 120 min were 47.59, 171.2, 223.5, 218.1, 199.8, 145.9, and 124.6 µIU/mL, respectively.
Additionally, the baseline and peak TSH levels were 47.59 and 223.5 µIU/mL, respectively.

Fig. 1 Clinical course of our patient
At infancy, he was administered 6–9 µg/kg/day of l-T4. At 7 years of age, he received a diagnosis for the clinicalclassification. His oral dosage of l-T4 was 5–7 µg/kg/day until 10 years of age, after which, the dosage waschanged to 3–4 µg/kg/day. At 15 years of age, treatment with l-T4 was temporarily discontinued, which resulted
in elevated TSH levels. At 18 years of age, he was orally administered 100 µg/day of l-T4.
Nagoya J. Med. Sci. 85. 369–374, 2023

370

doi:10.18999/nagjms.85.2.369

CH-associated TSHR p.Arg109Gln

Fig. 2 Direct sequence TSHR gene analysis
Sense 5'→3' direction; the case exhibits a heterozygous variant of c.326G > A (p.Arg109Gln) and c.1349G > A(p.Arg450His) in exons 4 and 10, respectively.

The patient was diagnosed with orthotopic, nongoitrous, and permanent CH. Other defects,
such as aplasia, hypoplasia, ectopic thyroid gland, defective hormone organification, and iodine
concentration deficiency were not observed. The patient continued taking l-T4 after undergoinga clinical examination at 7 years of age. At age 15 years, l-T4 in oral doses of 2.04 µg/kg/day
was temporarily discontinued, which resulted in increased TSH levels (15.9 µIU/mL). Thereafter,
the patient resumed the treatment, and his TSH levels returned to normal. Genetic analysis wasconducted to analyze the TSHR variant. Direct TSHR sequencing revealed p.Arg109Gln andp.Arg450His compound heterozygous variants, which were passed on from the father harboring
p.Arg109Gln and mother harboring p.Arg450His, respectively (Figure 2). At 18 years of age,the patient was 173.5 cm tall and weighed 54.2 kg, and he had oral administration of l-T4 at adose of 100 µg/day. He had not taken other medicines. His growth and psychomotor development
were within the normal range. Genetic TSHR analysis was useful to predict his further thyroid
function; therefore, he could understand the need for thyroid replacement therapy.

DISCUSSION
We report the case of a rare compound heterozygous variant associated with CH, where, forthe first time, the patient was followed-up till adolescence. This report reveals the clinical CHfeatures that are associated with TSHR p.Arg109Gln and p.Arg450His compound heterozygous
variants.
CH-associated TSHR p.Arg109Gln is a very rare variant. Clifton-Bligh et al first reported
that the TSHR p.Arg109Gln variant may lead to CH, with moderate functional deterioration.2
We identified six previous studies that reported TSHR p.Arg109Gln (Table 1).1-6 None of them
involved follow-up of patients until adolescence. No significant differences in sex were found in
the patients (males, 3; females, 4; unknown, 1). Patients with the TSHR p.Arg109Gln compound
heterozygous variant exhibit permanent CH,1,2,6 with high TSH levels and normal or slightly
lower fT4 levels. They are usually diagnosed during newborn screening. Patients with TSHR
Nagoya J. Med. Sci. 85. 369–374, 2023

371

doi:10.18999/nagjms.85.2.369

Daisuke Watanabe et al

Table 1Authors (year)

TSHR p.Arg109Gln variants in a previous reportCountry Age

Clifton-Bligh2(1997)

Diagnostic
TSH*
period(µIU/mL)

fT4*(ng/dL)

CP92

0.78

N/D

FA

3.9

0.87

NSex

Variants

3

M

TSHR p.R109Q/p.W546X

NBS

N/D

F

TSHR
p.R109Q/Wt

UK

Camilot3, Rapa4(2005, 2009)

Italy

N/D

N/D

TSHR
p.R109Q/Wt

Infancy

7.35

Normallevel

S

Nicoletti5 (2009)

Italy

N/D

F

TSHR
p.R109Q/Wt

Infancy

5.7

Normallevel

S

N/DFTSHR
p.R109Q/Wt

FA

5.6

Normallevel

N

N/D

F

TSHR
p.R109Q/Wt

FA

6.0

Normallevel

N

NBS

100<0.69

P

Fu6 (2016)

China

N/D

M

TSHR
p.R109Q/Wt
DUOX2
p.K530X

Sugisawa1 (2018)

Japan

12M

TSHR p.R109Q/p.R450H

NBS

131.2

P

Our case

Japan

18M

TSHR p.R109Q/p.R450H

NBS

411.59P

N/D: not detected
M: maleF: female
R: Arg
Q: Gln
W: Trp
X: XaaK: Lys
H: His
Wt: wild type
NBS: newborn screening
FA: family analysis
CP: clinical phenotype
N: normalS: subclinical CH
P: permanent CH* result at diagnosis

p.Arg109Gln monoallelic variants exhibit normal or subclinical CH with normal or slightly higher
TSH and normal fT4 levels.3-5 The father, harboring TSHR p.Arg109Gln heterozygous variant,in this case, had normal thyroid function in practice. CH-associated TSHR p.Arg109Gln may bemoderate in severity, as shown in previous functional analysis.1,2
Thus far, only one case of permanent CH-associated TSHR p.Arg109Gln and p.Arg450His
compound heterozygous variants has been reported in a 12-year-old Japanese boy.1 Our case wassimilar to this case because the patient had orthotopic, nongoitrous, and permanent CH; however,the I-123 uptake study results were different. The characteristic clinical feature was nonclassicalNagoya J. Med. Sci. 85. 369–374, 2023

372

doi:10.18999/nagjms.85.2.369

CH-associated TSHR p.Arg109Gln

TSH resistance, which is characterized by paradoxical I-123 uptake elevation. Nonclassical TSH
resistance is associated with genotype and TSH value.1 The patients had the same genotype and ahigh TSH value (47 µIU/mL); however, I-123 uptake had some differences. Our case may provide
useful information to elucidate the factors that are involved in nonclassical TSH resistance.
We performed the difficult task of following up on a patient with a rare variant for 18 years.
Hypothyroidism may become more apparent during puberty because of the increased thyroid
hormone demand.7 Our case showed that a small l-T4 amount was still needed although l-T4
could be steadily reduced by puberty. In the future, genotype identification could help predictthe long-term prognosis and reduce the requirement for detailed examinations.
Our report may not be novel enough because both p.Arg109Gln and p.Arg450His have beenreported in the literature. Particularly, the TSHR p.Arg450His allele seems a relatively common
variant site in permanent CH. Moreover, the TSHR p.Arg450His accounts for approximately 70%of the total TSHR identified variants among Japanese patients.8 However, further case studies ofthis kind are required to determine the relationship between gene variants and clinical features.9More case studies are needed to determine the relationship between genetic variants and clinicalfeatures in CH.

CONCLUSIONTSHR variant identification has provided important genetic information regarding CH. Patientswith TSHR p.Arg109Gln and p.Arg450His compound heterozygous variants exhibit permanent CHwith high TSH and normal or slightly low free-T4 levels. Patients with CH should be followed-up
in the long-term and genotype-phenotyped to contribute to future analysis.

AUTHOR CONTRIBUTION
Daisuke Watanabe wrote the first draft of this manuscript.

ETHICAL STANDARDS AND INFORMED CONSENT
We received ethical committee approval from our hospital and informed consent from thepatient’s parents. Written informed consent was obtained from the patient for publication ofthis case report.

CONFLICTS OF INTEREST
The authors declare no conflicts of interest.

FUNDING
No grant or payment was received to produce this manuscript.

Nagoya J. Med. Sci. 85. 369–374, 2023

373

doi:10.18999/nagjms.85.2.369

Daisuke Watanabe et alREFERENCES
12

3

4

5

6789

Sugisawa C, Abe K, Sunaga Y, Taniyama M, Hasegawa T, Narumi S. Identification of compoundheterozygous TSHR mutations (R109Q and R450H) in a patient with nonclassic TSH resistance and functional characterization of the mutant receptors. Clin Pediatr Endocrinol. 2018;27(3):123–130. doi:10.1297/
cpe.27.123.
Clifton-Bligh RJ, Gregory JW, Ludgate M, et al. Two novel mutations in the thyrotropin (TSH) receptor
gene in a child with resistance to TSH. J Clin Endocrinol Metab. 1997;82(4):1094–1100. doi:10.1210/
jcem.82.4.3863.
Camilot M, Teofoli F, Gandini A, et al. Thyrotropin receptor gene mutations and TSH resistance:
variable expressivity in the heterozygotes. Clin Endocrinol (Oxf). 2005;63(2):146–151. doi:10.1111/j.13652265.2005.02314.x.
Rapa A, Monzani A, Moia S, et al. Subclinical hypothyroidism in children and adolescents: a wide rangeof clinical, biochemical, and genetic factors involved. J Clin Endocrinol Metab. 2009;94(7):2414–2420.
doi:10.1210/jc.2009-0375.
Nicoletti A, Bal M, De Marco G, et al. Thyrotropin-stimulating hormone receptor gene analysis in pediatricpatients with non-autoimmune subclinical hypothyroidism. J Clin Endocrinol Metab. 2009;94(11):4187–4194.
doi:10.1210/jc.2009-0618.
Fu C, Wang J, Luo S, et al. Next-generation sequencing analysis of TSHR in 384 Chinese subclinicalcongenital hypothyroidism (CH) and CH patients. Clin Chim Acta. 2016;462:127–132. doi:10.1016/j.
cca.2016.09.007.
Weber G, Vigone MC, Stroppa L, Chiumello G. Thyroid function and puberty. J Pediatr Endocrinol Metab.
2003;16(Suppl 2):253–257.
Narumi S, Muroya K, Abe Y, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: apopulation-based genetic epidemiology study. J Clin Endocrinol Metab. 2009;94(4):1317–1323. doi:10.1210/jc.2008-1767.
Watanabe D, Hasebe Y, Kasai S, et al. PTPN11 c.853T>C (p.Phe285Leu) mutation in Noonan syndrome
with chylothorax. Nagoya J Med Sci. 2022;84(4):871–876. doi:10.18999/nagjms.84.4.871.

References EndNagoya J. Med. Sci. 85. 369–374, 2023

374

doi:10.18999/nagjms.85.2.369