Details Of Published TSH Receptor Mutation

Met 453 Thr

c.1358T>C

Constitutively Activating TSH Receptor Mutation

Type
gain
Manifestation
sporadic
Exon
10
Pedigree 1 (De Roux et al.)
-image missing-
Pedigree 2 (Lavard et al.)
-image missing-
Legend:
Male
Female
Unknown
Deceased
+
Mutation
-
No Mutation
Hyperthyroidism
(Heterozygous)
Goiter
Relapse
P
Index Patient
Molecular Characteristics:
sporadic occurrence in 3 non-related children

P1/II/1: De Roux et al.
P2/II/1: Lavard et al.

Tomonaga et al. cardiac failure at birth due to tachycardia
 
Clinical Features:
P1/II/1: De Roux et al.:
onset: P1/II/1: fetal, premature birth (32.5 weeks)

diagnosis:
P1/II/1: neonatal,
goiter at birth, eyelid retraction, hypertrophy of retroorbital tissue (CT), advanced bone age


P2/II/1:Lavard et al.:
onset: P2/II/1: fetal, premature birth (36 weeks)

diagnosis:
P2/II/1: 7 months,
multinodular goiter at 7yr, regression of staring eyes with control of thyrotoxicosis, learning difficulties, advanced bone age

diagnosis:
III/2: 8 months (index patient), diffuse goiter
III/3: neonatal
II/3: neonatal

III/2: mild facial hypoplasia, advanced bone age, motor and speech delay
III/3: cholestatic jaundice, generalized petechial hemorrhage

III/3,2, II/2: ventriculomegaly, shortening of the 5th metacarpal bones and of the middle phalanges of the 5th finger, advanced bone age, hepatosplenomegaly, exophthalmos, scaphocephaly

*based on 34 hot nodules investigated by Parma et al. 1997, Duprez et al. 1997, Trülzsch et al. 2001, Gozu et al. 2006, Georgopulos et al. 2003, Vanvooren et al. 2002, Kraemer et al. 2009, Paloz-Paz et al. 2009 and Nishihara et al. 2009
and 3 sporadic activating germline mutations investgated by de Roux et al. 1996 and Lavard et al. 1999
and Tomonga et al 2018 and 1 familial activating germline mutation investigated by Supornsilchai et al. 2009
and 1 hot thyroid carcinoma investigated by Mircescu et al. 2000 
Treatment:
P1/II/1: De Roux et al:
antithyroid drugs, L-T4







P2/II/1: Lavard et al.:
antithyroid drugs ineffective, subtotal TE at 9yr, repeated radioiodine from 9.5-13yr for treatment of toxic multinodular goiter
Functional Characteristics:
cAMP
(basal)
cAMP
(TSH)
IP
(basal)
IP
(TSH)
TSH-Binding
Cell Surface Expression
Prevalence
LRA
Ref
5.7-7.0
0.8
1.0
0.8-1.0
nd
0.66
3
5.2+/-0.8
Legend:
cAMP (basal): basal in vitro cAMP production of mutant over wild-type TSHR
cAMP (TSH): maximal in vitro cAMP production of mutant over wild-type TSHR
IP (basal): basal in vitro IP production of mutant over wild-type TSHR
IP (TSH): maximal in vitro IP production of mutant over wild-type TSHR
TSH-binding: maximal TSH-binding compared to the wild-type TSHR
Cell surface expression: cell surface expression of mutant compared to WT-TSHR
LRA: linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125I-bTSH binding or FACS analysis compared to the wild-type TSHR
Prevalence: Prevalence of (somatic and germline) activating mutations*
Ref: Reference for functional characterization
Child: Found in children.
Reference 1:
De Roux et al.
J. Clin. Endocrinol. Metab. 81: 2023-2026
A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism.
1996
Reference 2:
Lavard et al.
Hormone Research 51: 43-46
Long-Term Follow-Up of an Infant with Thyrotoxicosis due to Germline Mutation of the TSH Receptor gene (Met453Thr)
1999
Reference 3:
Jäschke et al.
Cell Mol Life Sci 65:4028-4038
Preferences of transmembrane helices for cooperative amplification of G(alpha)s and G (alpha)q signaling of the thyrotropin receptor.
2008
Reference 4:
Lüblinghoff et al.
J Endocrinol Invest 33:228-233
Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism.
2010
Reference 5:
Tomonaga et al.
Journal of Pediatric Surgery Case Reports
A case of congenital autonomous thyroid adenoma with a somatic activating gene mutation in the thyroid-stimulating hormone receptor
2018