Molecular and Cellular Endocrinology 322 (2010) 125–134
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enetics and phenomics of inherited and sporadic non-autoimmuneyperthyroidism
ulya Iliksu Gozua,∗, Julia Lublinghoffb, Rifat Bircanc, Ralf Paschkeb
Section of Endocrinology and Metabolism, Vakif Gureba Education and Research Hospital, Istanbul, TurkeyDepartment of Internal Medicine III, University of Leipzig, GermanyNamık Kemal University, Faculty of Arts and Sciences, Division of Biology, Department of Molecular Biology, 59030, Tekirdag, Turkey
r t i c l e i n f o
rticle history:eceived 26 June 2009eceived in revised form 31 January 2010ccepted 1 February 2010
eyword:ermline TSH receptor mutations
a b s t r a c t
TSH receptor (TSHR) germline mutations occur as activating mutations in familial non-autoimmunehyperthyroidism (FNAH) or sporadic non-autoimmune hyperthyroidism (SNAH). Up to date 17 con-stitutively activating TSHR mutations have been reported in 24 families with FNAH. The diagnosis ofFNAH should be considered in cases with a positive family history, early onset of hyperthyroidism, goi-ter, absence of clinical stigmata of autoimmunity and recurrent hyperthyroidism. Moreover, 14 subjectswith sporadic non-autoimmune hyperthyroidism and 10 different TSH receptor germline mutations havebeen reported. The main characteristic of SNAH is a negative family history. Additional consequences ofprolonged neonatal hyperthyroidism (mental retardation, speech disturbances and craniosynostosis)have often been reported in SNAH. No genotype–phenotype relationship has been reported in patientswith germline TSHR mutations. There is no association of in vitro activities determined by linear regres-
sion analysis (LRA) and several clinical indicators of hyperthyroidism activity for SNAH. However, thecomparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutationsdoes show a significantly higher median LRA value for sporadic as compared to familial autosomal dom-inant hyperthyroidism. This finding is in line with the clinical impression of a more active clinical coursein patients with SNAH. However, additional genetic, constitutional or environmental factors are mostlikely responsible for the phenotypic variations of the disease and the lack of correlation between in vitro activities of the TSHR mutations and the severity of hyperthyroidism.
. Introduction et al., 2002) which has been reported to be 12–20%, usually fromheart failure (Ogilvy-Stuart, 2002). Neonatal thyrotoxicosis is pre-
Overt neonatal hyperthyroidism (HT) is rare and affects onlyne neonate out of 50,000 (Polak et al., 2006). Although neonatalhyrotoxicosis is a rare entity, it necessitates immediate treat-
ent because of its high mortality (Ogilvy-Stuart, 2002; Radetti
∗ Corresponding author at: Section of Endocrinology and Metabolism, Vakifureba Education and Research Hospital, Adnan Menderes Bulvarı, Vatan Cad. Fatih4093 Istanbul, Turkey. Tel.: +902166586775; fax: +902125346970.
dominantly caused by maternal Graves’ disease associated withtransplacental passage of maternal thyroid-stimulating antibod-ies (Ogilvy-Stuart, 2002; Radetti et al., 2002; Hung and Sarlis,2004; Peters and Hindmarsh, 2007) and is less frequently causedby mutations in the stimulatory G protein or in the thyrotropinreceptor (TSHR) inducing constitutive activation of intracellular
signaling cascades. The prevalence of Graves’ disease in preg-nant women is estimated to about 0.2%; however, only 1% ofthe babies born to mothers with Graves’ disease develop neona-tal Graves’ disease (Polak, 1998; Ogilvy-Stuart, 2002). Neonatal
hyrotoxicosis is a transient disorder and disappears with thelearance of the maternal antibodies (half life about 14 days)rom the neonate serum within the first 4 months of life. Fetalachycardia, increased fetal motility and intrauterine growth retar-ation are consequences of fetal thyrotoxicosis. Prematurity isrequent. Tachycardia, goiter, hyperexcitability, poor weight gain,epatomegaly, growth retardation, craniosynostosis, acceleratedone maturation, splenomegaly, stare and eyelid retraction aremong the most frequent clinical signs noticed after birth (Polak,998; Lafranchi and Hanna, 2005). The patients with neonatal thy-otoxicosis should be treated promptly either with methimazoleMMI) or propylthiouracil (PTU). Propranolol is helpful in slowinghe heart rate down and in reducing hyperactivity. Glucocorticoidshould be given to patients with severe neonatal thyrotoxico-is in order to inhibit the extrathyroidal conversion of T4 to T3nd to inhibit thyroid hormone secretion from the thyroid glandLafranchi and Hanna, 2005).
An even more uncommon type of neonatal hyperthyroidismesults from mutations in the stimulatory G protein or thehyrotropin receptor (TSHR) causing constitutive activation ofntracellular signaling cascades. These mutations may be inheriteds autosomal dominant non-autoimmune hyperthyroidism (NAH)also called familial or hereditary NAH) or occur sporadically asenovo mutations (also called congenital NAH or sporadic NAH)Gozu et al., 2009a,b). Tables 1 and 2 show references of all casesf SNAH and FNAH reported up to date. These germline mutationsre predominantly localized in the transmembrane segments of theSHR (see Fig. 1).
. Constitutive activation of TSH receptor signaling inducesereditary and sporadic non-autoimmune hyperthyroidism
The TSH receptor (TSHR) belongs to the superfamily of sevenransmembrane domain receptors coupled to G proteins (Kopp,001; Rodien et al., 2003). This gene is encoded by 10 exons whichpread over 60 kb on chromosome 14. The large part of the extra-ellular domain is encoded by nine exons. The carboxyterminalart of the extracellular domain (EC), the seven transmembraneomains (TMDs) and intracellular loops (ICLs) are encoded byxon 10. The polypeptide backbone is 764 amino acids in lengthRapoport et al., 1998; Kopp, 2001; Rodien et al., 2003). Bindingf TSH to its receptor leads via G proteins (G�s and G�/G�11)o activation of the adenylyl cyclase (AC) and phospholipase CPLC) signaling pathways, respectively. Somatic mutations in theSHR or the Gs alpha proteins constitutively activate the cAMPascade and induce growth and hyperfunction of the thyroidollicular cells and ultimately thyroid autonomy (Allgeier et al.,994; Paschke and Ludgate, 1997; Zeiger et al., 1997; Krohn etl., 2005; Eszlinger et al., 2007). The TSHR plays a pivotal role inhe pathogenesis of thyroid diseases with somatic mutations inoxic adenoma, toxic multinodular goiter (MNG) or autonomouslyunctioning thyroid carcinoma. Furthermore, TSHR germline muta-ions occur in familial non-autoimmune hyperthyroidism (FNAH),poradic non-autoimmune hyperthyroidism (SNAH) and as inacti-ating mutations in certain forms of resistance to TSH (Gozu et al.,008).
. Clinical hallmarks of inherited non-autoimmuneyperthyroidism
Although various features have been described in different fam-lies, they share the common characteristics:
Clinical and biochemical stigmata of thyroid autoimmunity arebsent in familial non-autoimmune hyperthyroidism. No circulat-ng thyroid antibodies (including TSH receptor antibodies) were
ndocrinology 322 (2010) 125–134
detected in these patients.A positive family history for NAH is the pathognomonic feature
of FNAH. Familial non-autoimmune hyperthyroidism segregates inthe families with constitutively activating TSHR mutations and theclinical signs of hyperthyroidism are present in at least two gener-ations in the same family.
The Nancy pedigree describes the original family which lead tothe definition of FNAH (Thomas et al., 1982). In this family from theNorthern part of France thyrotoxicosis was observed in 16 of 48examined family members. Twelve years after the initial descrip-tion of this family, a heterozygous V509A germline mutation withhigher basal activation of adenyl cyclase than the wild type TSHRwas detected in six hyperthyroid family members.
In the Reims family also originating from Northern part of Francebut unrelated to Nancy family, 18 subjects were identified as clin-ically and biologically hyperthyroid. A C672Y replacement in theseventh transmembrane segment of the TSHR was reported in fiveaffected family members (Duprez et al., 1994).
Furthermore one unrelated family (Belfort family) with hyper-thyroidism and thyroid hyperplasia was reported (Tonacchera etal., 1996). In the Belfort family hyperthyroidism was identified infive patients in three generations. In this family, three membersdisplayed an A to T transversion causing a N650Y substitution.
Since its initial description, 17 constitutively activating TSHRmutations have been found in 24 families with FNAH.
All reported 90 (see Table 1) patients in 24 families with a TSHRgermline mutation were hyperthyroid, except two members inthe Nancy family (Thomas et al., 1982); one member in the fam-ily reported by Vaidya et al., 2004; three members in the familydescribed by Nishihara et al., 2007; one member of the familyreported by Pohlenz et al., 2006 and two members in the fam-ily reported by Arturi et al., 2002 who initially showed subclinicalhyperthyroidism or euthyroidism.
Although hyperthyroidism is a characteristic clinical finding, itsdegree varies from mild forms without overt symptoms of thyro-toxicosis or thyroid ophthalmopathy and hyperthyroidism easilycontrolled by antithyroid drugs (Lee et al., 2002) or subclinicalhyperthyroidism (Thomas et al., 1982; Arturi et al., 2002; Pohlenzet al., 2006; Vaidya et al., 2004; Nishihara et al., 2007) to severehyperthyroidism with severe complications of FNAH such as facialhypoplasia, advanced bone age, motor and speech delay, jaun-dice, petechial hemorrhage, cerebral ventriculomegaly, shorteningof fingers, hepatosplenomegaly and scaphocephaly necessitatingrepeated radioiodine therapy (Supornsilchai et al., 2009).
The age of manifestation of hyperthyroidism varies from theneonatal period to 60 years (Karges et al., 2005). It is also highlyvariable within the same family; 10–36 years in the Nancy family(Thomas et al., 1982), 18 months to 53 years in the Reims family(Duprez et al., 1994), 2–21 years in the Cardiff family (Führer et al.,2000) and 4–60 years in the family reported by Karges et al., 2005(all described in http://innere.uniklinikum-leipzig.de/tsh, see alsoTable 1).
Later onset of hyperthyroidism was the most important findingof autosomal dominant FNAH. However, neonatal manifestation ofNAH was also described in five families. In the 24 analyzed kindred5 of 90 examined patients were found to have hyperthyroidismwith neonatal onset (Führer et al., 1997; Schwab et al., 1997;Ringkananont et al., 2006; Akcurin et al., 2008; Supornsilchai et al.,2009). The index patient of the Leipzig family (Führer et al., 1997)was prematurely born at the 33rd week of gestation. Diarrhea, irri-tability, easy sweating and advanced bone age were established in
the neonatal period. Hyperthyroidism was diagnosed with goiterat 2 years when this patient presented with thyroid storm. Thisis also the only family with FNAH presenting with thyroid storm.Another family with FNAH with neonatal onset was identified inGermany (Schwab et al., 1997). Persistent hyperthyroidism was
127Table 1Clinical characteristics of subjects with autosomal dominant non-autoimmune hyperthyroidism and published specific constitutive activity of 17 mutations found in 24 families.
Supornsilchai et al. (2009) 7a 3 Facial hypoplasia,advanced bone age, motorand speech delay, jaundice,petechial hemorrhage,cerebral vetriculomegaly,shortening of fingers,hepatosplenomegaly,scaphocephaly,craniosynostosis
DG in 1 (8 y) At birth-8 m + + +
M463VATG → GTG
Führer et al. (2000) (Cardifffamily)
2 8 Advanced bone age, precoxpuberty (corresponding to9.1 y at 5 y), ectopicpregnancies, stillbirthduring thyrotoxicosis
DG in 8 (2, 4, 5, 7, 9,13, 20, 21 y)
2–21 y + + −
Lee et al. (2002) – 2 No goiter 2 y 7 m to 20 y + − −Arturi et al. (2002) 3 8 Two members were
euthyroidDG in 5 (11, 12, 14, 14,18 y), MNG in 3 (12,14, 17 y)
11–18 y + + +
Ferrara et al. (2007) – 4 Prominent eyes DG in 4 (8, 18, 27,30 y)
8–30 y + + −
A485VGCC → GTC
Akcurin et al. (2008) – 3 DG in 3 (12 d, 3 y 5 m,36 y)
12 d to 36 y + + −
S505NAGC → AAC
Vaidya et al. (2004) 4.9–6.5a 3 Prematurity (33 and 30 w),LBW (1750, 750 g),Advanced bone age (5.8 at3 y and 8 y at 5.5 y)gastro-oesophagal withsubclinicalhyperthyroidism
DG in 1 (19 m, toxicnodule at 8 y), DG in 1(9 y)
19 m to 9 y + + −
S505RAGC → AGA
Horton and Scazziga (1987)(Lausanne family)
2.2–2.7a 5 – DG in 5 (childhood-adolescence)
Childhood-adolescence
+ + +
Pohlenz et al. (2006) – 2 1 Patient with subclinicalhyperthyroidism
No goiter 6 m to 9 y + + −
V509AGTG → GCG
Thomas et al. (1982) (Nancyfamily)
3a 6 2 Members with subclinicalhyperthyroidism
DG in 10 (10, 14, 14,14, 19, 24, 25, 30, 34,36 y)
10–36 y + + +
Karges et al. (2005) 2.8 3 Advanced bone age(corresponding to 5.5 y at4 y)
DG in 1 (4 y), MNG in2 (18, 60 y)
4–60 y + + +
I568VATC → GTC
Claus et al. (2005) (Leipzig-2family)
2.5–2.9a 2 – DG in 1 (16 y), MNG in1 (25 y)
16–25 y + + +
V597FGTC → TTC
Alberti et al. (2001) 2 3 DG in 4 (5, 7, 16, 18 y) 5–18 y + + −
D617YGAC → TAC
Nishihara et al. (2007) 2.5 6 3 Members with subclinicalhyperthyroidism
DG in 3 (20, 20, 21 y) 20–55 y + + −
A623VGCC → GTC
Schwab et al. (1997) 4.2a 3 LBW, hyperbillurubinemia,advanced bone age(corresponding to 1 age at1 y)
DG in 1 (3 y), MNGrecurrence
3.5 w to 3 y + + −
128 H.I. Gozu et al. / Molecular and Cellular E
Tabl
e1
(Con
tinu
ed)
Mu
tati
onR
efer
ence
Bas
alcA
MP
fold
over
wil
dty
pe
TSH
R(w
t=1)
Ind
ivid
ual
sw
ith
mu
tati
onA
dd
itio
nal
feat
ure
sPr
esen
ceof
goit
er(a
geof
dia
gnos
is;
y,m
orw
)(G
,DG
,MN
G)
Age
ofd
iagn
osis
for
hyp
erth
yroi
dis
mTr
eatm
ent
wit
h
ATD
Surg
ery
Rad
I
M62
6IA
TG→
ATC
Rin
gkan
anon
tet
al.(
2006
)3.
55
–D
Gin
1(1
5m
)N
eon
atal
-30
y+
+−
ATG
→A
TAJä
sch
keet
al.(
2010
)2
No
goit
erre
por
ted
0.5–
10y
++
+
L629
FTT
G→
TTT
Füh
rer
etal
.(19
97)
(Lei
pzi
gfa
mil
y)2.
1–6.
5a2
Prem
atu
rity
(33
w),
cran
iosy
nos
tosi
s,ad
van
ced
bon
eag
ean
dth
yroi
dst
orm
DG
in1
(2y)
,DG
in1
inea
rly
chil
dh
ood
MN
Gat
18y)
Neo
nat
al-e
arly
chil
dh
ood
++
+
F631
STT
C→
TCC
Nw
osu
etal
.(20
06)
74
Prop
tosi
sin
ind
exp
atie
nt
pre
mat
uri
ty(3
0w
),ce
rebr
alp
alsy
in1
pat
ien
t
DG
in2
(42
and
19y)
,M
NG
(11
y)an
dn
ogo
iter
inth
eot
her
mem
ber
10–4
2y
+−
+
P639
SC
CA
→T C
AK
hoo
etal
.(19
99)
4.8–
5a1
Mit
ralv
alve
pro
lap
se,m
ild
pro
pto
sis
DG
in3
(5y
6m
,5y
8m
,10
y)5–
38y
++
−
N65
0YA
AC
→T A
CTo
nac
cher
aet
al.(
1996
)(B
elfo
rtfa
mil
y)2.
63
–D
Gin
2(1
4,23
y),
MN
Gin
114
–23
y+
+−
C67
2YTG
T→
TAT
Du
pre
zet
al.,
1994
(Rei
ms
fam
ily)
2.2
5–
DG
in5
(18
m,<
10y,
<10
y,19
y,53
y)18
mto
53y
++
+
Abb
revi
atio
ns:
G,D
G,N
G,M
NG
:go
iter
,dif
fuse
goit
er,n
odu
lar
goit
er,m
ult
inod
ula
rgo
iter
,res
pec
tive
ly;
w:
wee
kor
wee
ks;
y:ye
aror
year
s;m
:m
onth
s;LB
W:
low
birt
hw
eigh
t;SV
T:su
pra
ven
tric
ula
rta
chyc
ard
ia;
n.d
.:n
od
ata.
�th
em
uta
nt
nu
cleo
tid
ean
dam
inoa
cid
sequ
ence
sw
ere
des
crib
edac
cord
ing
toth
ere
com
men
dat
ion
sfo
ra
Nom
encl
atu
reSy
stem
for
Hu
man
Gen
eM
uta
tion
sw
hic
his
des
crib
edby
An
ton
arak
is(2
002)
.a
Fun
ctio
nal
char
acte
rist
ics
ofth
ese
germ
lin
em
uta
tion
sw
ere
not
des
crib
edin
thos
est
ud
ies
orad
dit
ion
alfu
nct
ion
ald
ata
for
thes
em
uta
tion
sw
ere
desc
ribe
din
oth
erst
ud
ies.
Soth
ed
ata;
des
crib
ing
the
fun
ctio
nal
char
acte
rist
ics
ofth
ese
mu
tati
ons
wer
eob
tain
edfr
omth
ean
oth
erst
ud
ies
des
crib
edin
htt
p:/
/in
ner
e.u
nik
lin
iku
m-l
eip
zig.
de/
tsh
/an
dh
ttp
://w
ww
.ssf
a-gp
hr.
de/
mai
n/s
sfa.
ph
p(K
lein
auet
al.,
2007
).
ndocrinology 322 (2010) 125–134
diagnosed in the mother at the age of 3 years with diffuse goi-ter (DG). Her second son showed hyperthyroidism at 3.5 weeksof life. Low birth weight and hyperbilirubinemia were the otherclinical signs of hyperthyroidism in this patient. Although onsetof hyperthyroidism was early and severe in the neonates of thesetwo families, antithyroid drug therapy was successful in controllinghyperthyroidism, but subtotal thyroidectomy and/or radioiodinetreatment were performed in the other family members because ofrecurrent hyperthyroidism.
The goiters are generally diffuse in children and tend tobecome multinodular later in life as described for several families(Tonacchera et al., 1996; Führer et al., 1997; Schwab et al., 1997;Arturi et al., 2002; Vaidya et al., 2004; Claus et al., 2005; Karges etal., 2005, all described in http://innere.uniklinikum-leipzig.de/tsh,see also Table 1). Diffuse goiter was reported in 59 out of 90 patientswith germline TSH receptor mutations in familial non-autoimmunehyperthyroidism. Multinodular goiter recurred in three of them(Führer et al., 1997; Schwab et al., 1997; Vaidya et al., 2004).Moreover, eight of the patients with familial non-autoimmunehyperthyroidism showed multinodular goiter later in life. Apartfrom this, goiter is not a consistent manifestation of FNAH. Goi-ter was not detected in 23 of 90 examined patients with familialnon-autoimmune hyperthyroidism (Schwab et al., 1997; Lee et al.,2002; Vaidya et al., 2004; Elgadi et al., 2005; Pohlenz et al., 2006;Ringkananont et al., 2006; Nwosu et al., 2006; Nishihara et al., 2007;Supornsilchai et al., 2009; Jäschke et al., 2010).
Multiple relapses after antithyroid drug therapy, thyroidec-tomy or radioiodine treatments are frequent in inheritednon-autoimmune hyperthyroidism. Radioiodine treatment wasadministrated in ten families because of multiple relapses ofhyperthyroidism after antithyroid drug treatment and/or thyroidsurgeries (Thomas et al., 1982; Horton and Scazziga, 1987; Duprezet al., 1994; Führer et al., 1997; Arturi et al., 2002; Claus et al., 2005;Karges et al., 2005; Nwosu et al., 2006; Supornsilchai et al., 2009;Jäschke et al., 2010). But recurrence of thyrotoxicosis even afterradioiodine treatment was also reported for one patient (Hortonand Scazziga, 1987).
Thyrotoxicosis involves in many of the organ systems includingneuropsychiatric manifestations, neuromuscular, cardiovascular,skeletal, gastrointestinal and reproductive systems.
Various clinical manifestations have been described in differ-ent families such as morning stiffness and pain in the lower limbs(Elgadi et al., 2005), cerebral palsy (Nwosu et al., 2006), hyper-active behavior, sleeping difficulties and enuresis (Biebermann etal., 2001), motor and speech delay (Supornsilchai et al., 2009),supraventricular tachycardia (Elgadi et al., 2005) and mitral valveprolapse (Khoo et al., 1999), advanced bone age (Führer et al.,1997; Schwab et al., 1997; Führer et al., 2000; Karges et al., 2005;Supornsilchai et al., 2009), facial hypoplasia, ventriculomegalyand scaphocephaly (Supornsilchai et al., 2009), craniosynostosis(Führer et al., 1997), hepatosplenomegaly, jaundice (Supornsilchaiet al., 2009) and hyperbiluribinemia (Schwab et al., 1997), prematu-rity (Führer et al., 1997; Vaidya et al., 2004; Nwosu et al., 2006) andlow birth weight (Vaidya et al., 2004; Supornsilchai et al., 2009).
The hereditary TSHR germline mutations display a 2.0 (M463V)to 7-fold (F631S and M453T) increase of basal cAMP over the wildtype TSHR (see Table 1). Theoretically the level of constitutive activ-ity of a TSHR mutation might influence the phenotype of disease. Alow SCA activity of a germline mutation could require a longer timeto induce thyrotoxicosis than mutations with a more pronouncedactivity.
No genotype–phenotype relationship has been reported inpatients with germline TSHR mutations.
Lower constitutive activity did not consistently correlate withlater onset of hyperthyroidism for sporadic TSHR mutations(Lüblinghoff et al., 2009). This is also true for familial TSHR
Presence of goiter(age of diagnosis)(G, DG, MNG, NG)
Treatment with
ATD Surgery Rad I
S281NAGC → AAC
Gruters et al. (1998) 3.5 + (36 w) − (2520 g) 4 m Craniosynostosis,premature birth, staringeyes
No goiter + + −
Chester et al. (2008) + (34 w) − (2350) 4 m Tachycardia, tachypnea,craniosynostosis, advancedbone age, midfacehypolasia, dolichocephaly,laryngomalacia and staringeyes
DG (4 m) + − −
A428VGCT → GTT
Borgel et al. (2005) 6.4* − (37 w) − (2550 g) Neonatal – G (4.5 y) + − −
M453TATG → ACG
de Roux et al. (1996) 7 + (32.5 w) − (1690 g) Neonatal Advanced bone age,hepatosplenomegaly,jaundice, premature birth,thrombocytopenicpurpura, proptosis, stareand eyelid retraction
DG in neonate + − −
Lavard et al. (1999) + (36 w) − (3040 g) 8 m Advanced bone age,delayed pubertal andpsychomotoricaldevelopment, mentalretardation, prematurebirth, splenomegaly,proptosis, staring eyes
MNG (7 y) + + +
S505NAGC → AAC
Holzapfel et al. (1997) 4–5 − (38 w) + (2600 g) 5 m Advanced bone age,craniosynostosis, growthretardation, mentalretardation, proptosis
DG (15 m) + + −
Führer et al. (1999) 5* − (40 w) + (2540 g) 11 m Advanced bone age, atopicdermatitis, growthretardation, low birthweight
DG (4.5 y) + − −
L512QCTG → CAG
Nishihara et al. (2006) 5 + (32 w) − (1860 g) Neonatal Advanced bone age (5 y at5 m), craniosynostosis(surgery forcraniosynostosis), internalhydrocephalus, mentalretardation, prematurebirth, very large goiter
DG (20 y) + − +
I568TATC → ACC
Tonacchera et al. (2000) 5.2 + (35 w) + (2050 g) 5.5 w Advanced bone age,accelerated staturalgrowth, premature birth,speech disturbance andstare/eye lid retraction,mental retardation
DG (5.5 w) + − −
Watkins et al. (2008) + (35 w) − (2557 g) Neonatal Meconium aspiration,pneumothorax,hepatomegaly, sleepdifficulties, hyperactivity,advanced bone age
No goiter + − −
V597LGTC → TTC
Esapa et al. (1999) 2.4 − (37 w) − (2500 g) 9 m Advanced bone age(corresponding 4 y at 10 m,low weight at 9 m (<4thpercentile)
DG (9 m) + + −
130 H.I. Gozu et al. / Molecular and Cellular ETa
ble
2(C
onti
nued
)
Mu
tati
onA
uth
orB
asal
cAM
Pfo
ldov
erba
salc
AM
Pof
wt
TSH
R(w
t=1)
Prem
atu
re+/
−(w
)LB
W+/
−(g
)A
geof
dia
gnos
isof
hyp
erth
yroi
dis
mC
onse
quen
ces
ofn
eon
atal
hyp
erth
yroi
dis
mPr
esen
ceof
goit
er(a
geof
dia
gnos
is)
(G,D
G,M
NG
,NG
)
Trea
tmen
tw
ith
ATD
Surg
ery
Rad
I
F631
LT T
C→
CTC
Kop
pet
al.(
1995
)5–
6+
(32
w)
−(1
660
g)N
eon
atal
Hyp
erac
tivi
ty,m
enta
lre
tard
atio
n,p
rem
atu
rebi
rth
,ad
van
ced
bon
eag
e
DG
inn
eon
ate,
MN
G(8
y)+
++
T632
IA
CC
→A
TCK
opp
etal
.(19
97)
3.7–
5.0*
+(3
3w
)+
(145
0g)
Neo
nat
alLo
wbi
rth
wei
ght,
men
tal
reta
rdat
ion
,pre
mat
ure
birt
h,p
ossi
ble
cere
bral
dys
gen
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ndocrinology 322 (2010) 125–134
mutations. Hyperthyroidism can begin during the neonatal periodalthough the increase of basal cAMP was low (e.g. a 4-fold basalcAMP increase for A623V was associated with early onset ofHT from the neonatal period to 3 years; Schwab et al., 1997).Likewise higher basal cAMP accumulation was not consistentlyassociated with earlier onset of disease. Basal cAMP accumula-tion of S505N (5-fold) and P639S (5-fold) were high, but the ageof onset of hyperthyroidism was at 19 months to 9 years (Vaidyaet al., 2004) and 5–38 years (Khoo et al., 1999) in these patients,respectively.
Moreover the patients of the same family carrying the sameTSHR germline mutation showed large differences in the onsetand/or severity of the disease (Arturi et al., 2002; Vaidya et al.,2004; Thomas et al., 1982 for M463V, S505N and V509A, respec-tively). Similarly, various phenotypes were also identified in thedifferent families harboring the same germline TSHR mutations(Thomas et al., 1982; Horton and Scazziga, 1987; Führer et al., 2000;Biebermann et al., 2001; Arturi et al., 2002; Lee et al., 2002; Elgadiet al., 2005; Karges et al., 2005; Pohlenz et al., 2006; Ferrara et al.,2007).
Except from the absence of clinical signs of thyroid autoimmu-nity, the presence of a positive family history for non-autoimmunehyperthyroidism and the presence of an active clinical course withmultiple relapses of hyperthyroidism under antithyroid medicationand even after radioiodine therapy and/or non-total thyroidectomyfor the majority of the patients, no specific clinical features can bedescribed for patients with FNAH. The fact that no direct relationof the in vitro activity of the TSHR mutation (basal cAMP value)and the age at onset of HT and the severity of clinical course wasfound and that even for the same TSHR mutation different clinicalcourses in different families were described suggests that the clin-ical course is more likely influenced by further genetic/epigeneticand environmental factors than by the in vitro activity of the TSHRmutation itself.
4. Clinical hallmarks of sporadic non-autoimmunehyperthyroidism
Clinical characteristics of the subjects with sporadic non-autoimmune hyperthyroidism are described in Tables 2 and 3 (seealso http://innere.uniklinikum-leipzig.de/tsh/for further details).
5. Sporadic non-autoimmune hyperthyroidism is moresevere than familial autosomal dominant hyperthyroidism
The family history for non-autoimmune hyperthyroidism isnegative in sporadic non-autoimmune hyperthyroidism. The phe-notype of a patient with congenital sporadic hyperthyroidism wasfirst described by Kopp et al. (1995). A thymidine to cytosine (T toC position) transition causing the substitution of leucine (CTC) forphenylalanine (TTC) at position 631 in one allele was identified inthe DNA from the patient’s leucocytes and nodular thyroid tissue.This mutation could not be detected in the patient’s parents andsister, showing that the patient had a de novo germline mutation.
Stigmata of autoimmunity and lymphocytic infiltration in thethyroid gland are absent in sporadic non-autoimmune hyperthy-roidism. Endocrine ophthalmopathy as an extraocular finding ofautoimmune hyperthyroidism has not been described in sporadicnon-autoimmune congenital hyperthyroidism except five patients(de Roux et al., 1996; Holzapfel et al., 1997; Kopp et al., 1997;Lavard et al., 1999; Bircan et al., 2008). Nevertheless, stare and eye-
lid retraction may be caused by congenital thyrotoxicosis (de Rouxet al., 1996; Gruters et al., 1998; Lavard et al., 1999; Tonacchera etal., 2000; Chester et al., 2008).
Onset of disease is earlier (neonatal period to 11 months) andmore severe than hereditary non-autoimmune hyperthyroidism.
H.I. Gozu et al. / Molecular and Cellular Endocrinology 322 (2010) 125–134 131
F e inhs ond es embl
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ig. 1. Localizations of the inherited/sporadic germline TSHR mutations. Most of thegment but several inherited germline tshr mutations are located in first and secporadic germline mutations also mostly located in first, second, third and fifth transmocated in extracellular domain and second extra cellular loop of the receptor.
atients with SNAH frequently presented with fetal or neonatalnset of hyperthyroidism (10 instead of 5 patients in FNAH). Con-enital sporadic hyperthyroidism can be very severe thus requiringrompt initial treatment in an intensive care unit (ICU) (Kopp et al.,997). Exceptionally, also a very mild course of hyperthyroidismas been reported for SNAH. The patient showed no consequencesf neonatal hyperthyroidism. Antithyroid treatment was successfuln controlling hyperthyroidism for the first 5.9 years of age (Borgelt al., 2005).
The thyroid size of patients with sporadic non-autoimmuneyperthyroidism is also variable. Nine of 14 patients presented aiffuse goiter at disease onset (see Table 2). With longer durationf the disease the diffuse goiter usually turns into a multinodularoiter (Kopp et al., 1995). Only two cases reported a nodular goi-er at first onset at 3 and 7 years, respectively (Kopp et al., 1997;avard et al., 1999). Moreover, a large thyroid volume of 370 ml at0 years was revealed by CT of the neck in one case (Nishihara etl., 2006). No goiter was reported in two cases with congenital spo-adic hyperthyroidism (Gruters et al., 1998; Watkins et al., 2008;ee Tables 2 and 3).
Hyperthyroidism commonly relapses following withdrawal ofntithyroid drugs and also after subtotal thyroidectomy. Therefore,ot only early diagnosis is important in congenital hyperthy-oidism, but also combined ablative regimens should be considered.arly combined treatment with near-total thyroidectomy plusadioiodine therapy have been reported to be the treatment ofhoice for some patients with sporadic non-autoimmune hyper-hyroidism (Kopp et al., 1995, 1997; Lavard et al., 1999). Moreoveradioiodine therapy was administrated four times from the age–13 years in the patient reported by Lavard et al. (1999).
Various consequences of prolonged neonatal hyperthyroidismncluding goiter, microcephaly, craniosynostosis, psychomotor dis-urbances, mental retardation, intrauterine growth retardation,rematurity, low birth weight, proptosis, stare, eyelid retractionnd advanced bone age have been reported.
erited TSHR mutations are located in first, second, third and fifth tramsmembranextracellular loop of the receptor. Besides the inherited germline TSHR mutations;rane segment with a few exceptions. Some of the sporadic germline TSHR mutations
In contrast to FNAH, the majority of the patients with sporadicNAH were prematurely born (10 of 14 patients) and some presentedwith low birth weight (4 of 14 patients) (see Tables 2 and 3).
Early and effective control of hyperthyroidism in these childrenwith an activating TSHR mutation is essential to prevent permanentpsychomotor retardation, advanced bone age and craniosynostosisand it’s complications as it is seen frequently in patients with SNAH(see Tables 2 and 3).
The germline mutations that caused congenital hyperthy-roidism were heterozygous and affected only one allele. However,also cases with a silent TSHR germline polymorphism (not display-ing constitutive activity in vitro) were described for two patientswith hyperthyroidism and with additional sporadic or somaticTSHR mutations, respectively. Gruters et al. (1998) identified aS281N sporadic germline mutation, thus explaining the severe con-genital hyperthyroidism in this patient. Additionally, the silentpolymorphism R528H. was detected in the index patient and in fouradditional family members. Moreover, Gozu et al. (2008) reported asilent germline mutation (N372T) together with the constitutivelyactive somatic TSHR mutation S281N in a hot thyroid nodule.
Congenital sporadic hyperthyroidism should be distinguishedfrom the more common familial autosomal dominant NAH in ordernot to miss timely therapy in genetically diagnosed family mem-bers and because of earlier onset of disease (neonatal period to11 months) and more severe clinical courses of SNAH than hered-itary NAH, causing irreversible consequences if untreated (Koppet al., 1995). Patients with SNAH were frequently presented withcomplications of fetal/neonatal hyperthyroidism like prematurity(10 instead of 4 patients in FNAH), craniosynostosis (6 instead of2 patients in FNAH), mental retardation (6 instead of 2 patients in
FNAH), advanced bone age (11 instead of 7 patients in FNAH), fre-quent relapses of hyperthyroidism after antithyroid drugs, thyroidsurgery and radioiodine therapy (8 patients in SNAH). Patients withfamilial NAH show milder clinical courses of hyperthyroidism oftencontrolled with antithyroid drugs and there are even family mem-
132 H.I. Gozu et al. / Molecular and Cellular Endocrinology 322 (2010) 125–134
Table 3Association of clinical signs of sporadic non-autoimmune hyperthyroidism with the LRA, modified according to Lüblinghoff et al. (2009).
Clinical sign Total number of patients withrespective clinical sign
Number of patients with low in vitroactivity: LRA < 15.1 (total number n = 6)
Number of patients with high in vitroactivity: LRA ≥ 15.1 (total number n = 8)
Duration of HT (in years)≤1 4 0d 41 < HT ≤ 3 3 2d 1HT > 3 6 3d 3
Active clinical coursee 8 4 4
a No goiter reported by Gruters et al. (1998) and Watkins et al. (2008).b Morphology of goiter not reported by Borgel et al. (2005).c The detailed follow-up of thyroid size in these three patients gives evidence for an excessive thyroid enlargement: Nishihara et al. (2006) reported a thyroid size of 370 ml
a at 12.3
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t 20 years; Holzapfel et al. (1997): 16 ml at 25 months; Führer et al. (1999): 48 mld No follow-up data for de Roux et al. (1996).e Frequent relapses of HT under antithyroid drug therapy, thyroid surgery an
rematurity, low birth weight, advanced bone age and mental retardation were cha
ers with subclinical hyperthyroidism or euthyroidism (9 patientsn FNAH).
Functional analysis of the de novo sporadic TSHR mutationshowed that basal cAMP accumulation of these mutations rangerom 2.4 (V597L) to 7 (M453T)-fold increase of basal cAMP com-ared with the wt TSHR (see Table 2). Patients with the sameporadic TSHR mutations showed completely different clinicalourses. A milder clinical course was described by de Roux et al.1996), Führer et al. (1999), and Tonacchera et al. (2000), whereasavard et al. (1999), Holzapfel et al. (1997) and Watkins et al. (2008)eported a severe clinical course with frequent relapses of hyper-hyroidism for patients with M453T, S505N and I568T, respectivelyLüblinghoff et al., 2009).
For better understanding of the constitutive activity of the TSHR,inear regression analysis (LRA) of constitutive activity as a func-ion of the TSHR expression was described as a more reliable wayo characterize the in vitro activity of a constitutively active TSHR
utation compared to the basal cAMP levels (Müller et al., 2009).o consistent relation of the LRA values of the sporadic TSHRutations and the clinical signs of patients with sporadic NAHas described (Lüblinghoff et al., 2009). Although high LRA val-es were found for some sporadic TSHR mutations (25.6 for I568Tnd 45.9 for F631L), these patients did not show an active clin-cal course compared to patients for which lower LRA values ofhe TSHR mutations were described (M453T with 5.2 and L512Qith 4.5). A mild clinical course with neonatal onset of hyperthy-
oidism was controlled with antithyroid drugs associated with a
568T mutation (Tonacchera et al., 2000). de Roux et al. (1996)nd Lavard et al. (1999) reported two unrelated patients with theSHR mutation M453T. Although the LRA of this mutation was veryow (with 5.2), both patients showed the fetal onset of hyperthy-oidism and were delivered before term. They might be classified
years.
adioiodine therapy plus complications of sporadic non-autoimmune HT such asristics of an active clinical course.
as active clinical course. For the patients described by de Roux etal. (1996), euthyroidism could be easly achieved with antithyroiddrugs. But medical treatment and subtotal thyroidectomy could notstop relapses of hyperthyroidism, so repeated ablative radioiodinetherapy was necessary on a patient with severe hyperthyroidismreported by Lavard et al. (1999). No clear evidence was diagnosedfor a consistent relation of the TSHR mutation’s in vitro activitydetermined by LRA with the clinical course of patients with SNAH.Moreover, the comparison of the clinical courses of the patientsharboring the same mutation also show no relation of the clini-cal activity with a high LRA. This was most likely due to differentdiagnostic circumstances and therapeutic strategies, limitations ofa systemic analysis of case reports due to limited follow-up andthe restricted case number of 14 patients. This may be also dueto action of genetic, epigenetic and environmental modifiers likeiodine supply (Lüblinghoff et al., 2009).
Furthermore, a more detailed analysis of all published casereports did also not show any association of in vitro activities deter-mined by LRA and several clinical indicators of hyperthyroidismactivity (Table 3, modified according to Lüblinghoff et al., 2009).However, the comparison of the median LRA values of all 14 pub-lished sporadic TSHR mutations with the 17 published LRA values of24 familial TSHR mutations did show a significantly higher medianLRA for sporadic as compared to familial autosomal dominanthyperthyroidism (Lüblinghoff et al., submitted for publication).This finding is in line with the clinical impression of a more activeclinical course in patients with sporadic NAH with earlier onset of
HT, severe complications of HT such as craniosynostosis and mentalretardation and an active clinical course with relapses of HT evenafter radioiodine therapy and/or thyroid surgery compared to theclinical course of patients with familial NAH. Furthermore, becauseof the low in vitro activity of the familial TSHR mutation the thy-
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oid tissue in patients with FNAH needs to reach a certain volumeo affect the patients’ phenotype thus explaining the later onset ofT in patients with FNAH compared to those with SNAH. Moreover,high in vitro activity of a familial TSHR mutation could very likely
ead to a more severe survival disadvantage and thus would be lessikely inherited by the next generation whereas the sporadic TSHRermline mutations occur as de novo mutations. Thus their mani-estation in the first generation is not affected by a similar negativeenetic selection.
There are several possible explanations for the differences foundetween TSHR genotype and clinical phenotype. G protein recep-or kinase2 (GRK2) and �-arrestin 1 are negative regulators ofhyrotropin receptor-stimulated response (Iacovelli et al., 1996).PRKs belong to a family of serine-threonine kinases which phos-horylate the agonist form of GPCR. The phosphorylated GPCRinds to a second family of proteins, termed �-arrestin leadingo receptor uncoupling and signal shut off (Penela et al., 2001;oigt et al., 2004). �-Arrestin-induced desensitization and down-egulation of the receptor is one of the possible explanations for thisiscrepancy. In line with this reasoning is the increased expressionf �-arrestin 2 that has been found in hot nodules (Voigt et al.,000). Moreover, variations in other signaling molecules like PDEs,-proteins, GRAPs, Adenylate cyclases, CREM, CREB, etc. are fur-
her possible explanations. Moreover, most likely additional factorsike the genetic back ground and/or iodine intake may modify thehenotypic expression (Trulzsch et al., 2001; Gozu et al., 2009a,b).
In conclusion, a rare form of persistent hyperthyroidism isaused by germline mutations in the TSH receptor in the absencef maternal autoimmunity. Germline-activating TSHR mutationsause sporadic congenital hyperthyroidism or non-autoimmuneamilial hyperthyroidism presenting with mild to severe clinicalourses of hyperthyroidism. No genotype–phenotype relations haseen reported in patients with germline TSHR mutations. Thisight be the effect of other genetic, epigenetic and environmental
actors. Delayed or inadequate treatment may aggravate develop-ental abnormalities due to hyperthyroidism in these children.
herefore, early recognition of such cases is important and appro-riate treatment and early diagnosis of the other family members
s necessary.
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hormone receptor activating mutation: case report and literature review.
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