Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism

Molecular and Cellular Endocrinology 322 (2010) 125–134

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Review

Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism Hulya Iliksu Gozu a,∗ , Julia Lublinghoff b , Rifat Bircan c , Ralf Paschke b a

Section of Endocrinology and Metabolism, Vakif Gureba Education and Research Hospital, Istanbul, Turkey Department of Internal Medicine III, University of Leipzig, Germany c Namık Kemal University, Faculty of Arts and Sciences, Division of Biology, Department of Molecular Biology, 59030, Tekirda˘g, Turkey b

a r t i c l e

i n f o

Article history: Received 26 June 2009 Received in revised form 31 January 2010 Accepted 1 February 2010 Keyword: Germline TSH receptor mutations

a b s t r a c t TSH receptor (TSHR) germline mutations occur as activating mutations in familial non-autoimmune hyperthyroidism (FNAH) or sporadic non-autoimmune hyperthyroidism (SNAH). Up to date 17 constitutively activating TSHR mutations have been reported in 24 families with FNAH. The diagnosis of FNAH should be considered in cases with a positive family history, early onset of hyperthyroidism, goiter, absence of clinical stigmata of autoimmunity and recurrent hyperthyroidism. Moreover, 14 subjects with sporadic non-autoimmune hyperthyroidism and 10 different TSH receptor germline mutations have been reported. The main characteristic of SNAH is a negative family history. Additional consequences of prolonged neonatal hyperthyroidism (mental retardation, speech disturbances and craniosynostosis) have often been reported in SNAH. No genotype–phenotype relationship has been reported in patients with germline TSHR mutations. There is no association of in vitro activities determined by linear regression analysis (LRA) and several clinical indicators of hyperthyroidism activity for SNAH. However, the comparison of the LRA values of sporadic TSHR mutations with LRA values of familial TSHR mutations does show a significantly higher median LRA value for sporadic as compared to familial autosomal dominant hyperthyroidism. This finding is in line with the clinical impression of a more active clinical course in patients with SNAH. However, additional genetic, constitutional or environmental factors are most likely 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. © 2010 Elsevier Ireland Ltd. All rights reserved.

Contents 1. 2. 3. 4. 5.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Constitutive activation of TSH receptor signaling induces hereditary and sporadic non-autoimmune hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . Clinical hallmarks of inherited non-autoimmune hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Clinical hallmarks of sporadic non-autoimmune hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sporadic non-autoimmune hyperthyroidism is more severe than familial autosomal dominant hyperthyroidism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction Overt neonatal hyperthyroidism (HT) is rare and affects only one neonate out of 50,000 (Polak et al., 2006). Although neonatal thyrotoxicosis is a rare entity, it necessitates immediate treatment because of its high mortality (Ogilvy-Stuart, 2002; Radetti

∗ Corresponding author at: Section of Endocrinology and Metabolism, Vakif Gureba Education and Research Hospital, Adnan Menderes Bulvarı, Vatan Cad. Fatih 34093 Istanbul, Turkey. Tel.: +902166586775; fax: +902125346970. E-mail address: [email protected] (H.I. Gozu). 0303-7207/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2010.02.001

125 126 126 130 130 133

et al., 2002) which has been reported to be 12–20%, usually from heart failure (Ogilvy-Stuart, 2002). Neonatal thyrotoxicosis is predominantly caused by maternal Graves’ disease associated with transplacental passage of maternal thyroid-stimulating antibodies (Ogilvy-Stuart, 2002; Radetti et al., 2002; Hung and Sarlis, 2004; Peters and Hindmarsh, 2007) and is less frequently caused by mutations in the stimulatory G protein or in the thyrotropin receptor (TSHR) inducing constitutive activation of intracellular signaling cascades. The prevalence of Graves’ disease in pregnant women is estimated to about 0.2%; however, only 1% of the babies born to mothers with Graves’ disease develop neonatal Graves’ disease (Polak, 1998; Ogilvy-Stuart, 2002). Neonatal

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thyrotoxicosis is a transient disorder and disappears with the clearance of the maternal antibodies (half life about 14 days) from the neonate serum within the first 4 months of life. Fetal tachycardia, increased fetal motility and intrauterine growth retardation are consequences of fetal thyrotoxicosis. Prematurity is frequent. Tachycardia, goiter, hyperexcitability, poor weight gain, hepatomegaly, growth retardation, craniosynostosis, accelerated bone maturation, splenomegaly, stare and eyelid retraction are among the most frequent clinical signs noticed after birth (Polak, 1998; Lafranchi and Hanna, 2005). The patients with neonatal thyrotoxicosis should be treated promptly either with methimazole (MMI) or propylthiouracil (PTU). Propranolol is helpful in slowing the heart rate down and in reducing hyperactivity. Glucocorticoids should be given to patients with severe neonatal thyrotoxicosis in order to inhibit the extrathyroidal conversion of T4 to T3 and to inhibit thyroid hormone secretion from the thyroid gland (Lafranchi and Hanna, 2005). An even more uncommon type of neonatal hyperthyroidism results from mutations in the stimulatory G protein or the thyrotropin receptor (TSHR) causing constitutive activation of intracellular signaling cascades. These mutations may be inherited as autosomal dominant non-autoimmune hyperthyroidism (NAH) (also called familial or hereditary NAH) or occur sporadically as denovo mutations (also called congenital NAH or sporadic NAH) (Gozu et al., 2009a,b). Tables 1 and 2 show references of all cases of SNAH and FNAH reported up to date. These germline mutations are predominantly localized in the transmembrane segments of the TSHR (see Fig. 1). 2. Constitutive activation of TSH receptor signaling induces hereditary and sporadic non-autoimmune hyperthyroidism The TSH receptor (TSHR) belongs to the superfamily of seven transmembrane domain receptors coupled to G proteins (Kopp, 2001; Rodien et al., 2003). This gene is encoded by 10 exons which spread over 60 kb on chromosome 14. The large part of the extracellular domain is encoded by nine exons. The carboxyterminal part of the extracellular domain (EC), the seven transmembrane domains (TMDs) and intracellular loops (ICLs) are encoded by exon 10. The polypeptide backbone is 764 amino acids in length (Rapoport et al., 1998; Kopp, 2001; Rodien et al., 2003). Binding of TSH to its receptor leads via G proteins (G␣s and G␣/G␣11) to activation of the adenylyl cyclase (AC) and phospholipase C (PLC) signaling pathways, respectively. Somatic mutations in the TSHR or the Gs alpha proteins constitutively activate the cAMP cascade and induce growth and hyperfunction of the thyroid follicular cells and ultimately thyroid autonomy (Allgeier et al., 1994; Paschke and Ludgate, 1997; Zeiger et al., 1997; Krohn et al., 2005; Eszlinger et al., 2007). The TSHR plays a pivotal role in the pathogenesis of thyroid diseases with somatic mutations in toxic adenoma, toxic multinodular goiter (MNG) or autonomously functioning thyroid carcinoma. Furthermore, TSHR germline mutations occur in familial non-autoimmune hyperthyroidism (FNAH), sporadic non-autoimmune hyperthyroidism (SNAH) and as inactivating mutations in certain forms of resistance to TSH (Gozu et al., 2008). 3. Clinical hallmarks of inherited non-autoimmune hyperthyroidism Although various features have been described in different families, they share the common characteristics: Clinical and biochemical stigmata of thyroid autoimmunity are absent in familial non-autoimmune hyperthyroidism. No circulating thyroid antibodies (including TSH receptor antibodies) were

detected in these patients. A positive family history for NAH is the pathognomonic feature of FNAH. Familial non-autoimmune hyperthyroidism segregates in the families with constitutively activating TSHR mutations and the clinical signs of hyperthyroidism are present in at least two generations in the same family. The Nancy pedigree describes the original family which lead to the definition of FNAH (Thomas et al., 1982). In this family from the Northern part of France thyrotoxicosis was observed in 16 of 48 examined family members. Twelve years after the initial description of this family, a heterozygous V509A germline mutation with higher basal activation of adenyl cyclase than the wild type TSHR was detected in six hyperthyroid family members. In the Reims family also originating from Northern part of France but unrelated to Nancy family, 18 subjects were identified as clinically and biologically hyperthyroid. A C672Y replacement in the seventh transmembrane segment of the TSHR was reported in five affected family members (Duprez et al., 1994). Furthermore one unrelated family (Belfort family) with hyperthyroidism and thyroid hyperplasia was reported (Tonacchera et al., 1996). In the Belfort family hyperthyroidism was identified in five patients in three generations. In this family, three members displayed an A to T transversion causing a N650Y substitution. Since its initial description, 17 constitutively activating TSHR mutations have been found in 24 families with FNAH. All reported 90 (see Table 1) patients in 24 families with a TSHR germline mutation were hyperthyroid, except two members in the Nancy family (Thomas et al., 1982); one member in the family reported by Vaidya et al., 2004; three members in the family described by Nishihara et al., 2007; one member of the family reported by Pohlenz et al., 2006 and two members in the family reported by Arturi et al., 2002 who initially showed subclinical hyperthyroidism or euthyroidism. Although hyperthyroidism is a characteristic clinical finding, its degree varies from mild forms without overt symptoms of thyrotoxicosis or thyroid ophthalmopathy and hyperthyroidism easily controlled by antithyroid drugs (Lee et al., 2002) or subclinical hyperthyroidism (Thomas et al., 1982; Arturi et al., 2002; Pohlenz et al., 2006; Vaidya et al., 2004; Nishihara et al., 2007) to severe hyperthyroidism with severe complications of FNAH such as facial hypoplasia, advanced bone age, motor and speech delay, jaundice, petechial hemorrhage, cerebral ventriculomegaly, shortening of fingers, hepatosplenomegaly and scaphocephaly necessitating repeated radioiodine therapy (Supornsilchai et al., 2009). The age of manifestation of hyperthyroidism varies from the neonatal period to 60 years (Karges et al., 2005). It is also highly variable 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 also Table 1). Later onset of hyperthyroidism was the most important finding of autosomal dominant FNAH. However, neonatal manifestation of NAH was also described in five families. In the 24 analyzed kindred 5 of 90 examined patients were found to have hyperthyroidism with 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, irritability, easy sweating and advanced bone age were established in the neonatal period. Hyperthyroidism was diagnosed with goiter at 2 years when this patient presented with thyroid storm. This is also the only family with FNAH presenting with thyroid storm. Another family with FNAH with neonatal onset was identified in Germany (Schwab et al., 1997). Persistent hyperthyroidism was

Table 1 Clinical characteristics of subjects with autosomal dominant non-autoimmune hyperthyroidism and published specific constitutive activity of 17 mutations found in 24 families. Mutation

Reference

Basal cAMP fold over wild type TSHR (wt = 1)

Individuals with mutation

Additional features

Presence of goiter (age of diagnosis; y, m or w) (G, DG, MNG)

Age of diagnosis for hyperthyroidism

ATD

Surgery

RadI

G431S GGC → AGC

Biebermann et al. (2001)

2.5–6.3a

3

Hyperactive behavior, tremor, sleeping difficulties and enuresis morning stiffness, pain in lower limbs, excessive sweating, SVT Facial hypoplasia, advanced bone age, motor and speech delay, jaundice, petechial hemorrhage, cerebral vetriculomegaly, shortening of fingers, hepatosplenomegaly, scaphocephaly, craniosynostosis Advanced bone age, precox puberty (corresponding to 9.1 y at 5 y), ectopic pregnancies, stillbirth during thyrotoxicosis

DG in 3 (3, 4, 15 y)

3y-Adolescence

+

+

−

No goiter in any patient

5y-Adulthood

+

+

−

DG in 1 (8 y)

At birth-8 m

+

+

+

DG in 8 (2, 4, 5, 7, 9, 13, 20, 21 y)

2–21 y

+

+

−

No goiter DG in 5 (11, 12, 14, 14, 18 y), MNG in 3 (12, 14, 17 y) DG in 4 (8, 18, 27, 30 y) DG in 3 (12 d, 3 y 5 m, 36 y) DG in 1 (19 m, toxic nodule at 8 y), DG in 1 (9 y)

2 y 7 m to 20 y 11–18 y

+ +

− +

− +

8–30 y

+

+

−

12 d to 36 y

+

+

−

19 m to 9 y

+

+

−

DG in 5 (childhoodadolescence) No goiter

Childhoodadolescence 6 m to 9 y

+

+

+

+

+

−

DG in 10 (10, 14, 14, 14, 19, 24, 25, 30, 34, 36 y) DG in 1 (4 y), MNG in 2 (18, 60 y)

10–36 y

+

+

+

4–60 y

+

+

+

DG in 1 (16 y), MNG in 1 (25 y) DG in 4 (5, 7, 16, 18 y)

16–25 y

+

+

+

5–18 y

+

+

−

DG in 3 (20, 20, 21 y)

20–55 y

+

+

−

DG in 1 (3 y), MNG recurrence

3.5 w to 3 y

+

+

−

Elgadi et al. (2005)

4

Supornsilchai et al. (2009)

7a

3

M463V ATG → GTG

Führer et al. (2000) (Cardiff family)

2

8

Lee et al. (2002) Arturi et al. (2002)

– 3

2 8

Ferrara et al. (2007)

–

4

Akcurin et al. (2008)

–

3

Vaidya et al. (2004)

4.9–6.5a

3

Horton and Scazziga (1987) (Lausanne family) Pohlenz et al. (2006)

2.2–2.7a

5

–

2

A485V GCC → GTC S505N AGC → AAC

S505R AGC → AGA

V509A GTG → GCG

I568V ATC → GTC V597F GTC → TTC D617Y GAC → TAC A623V GCC → GTC

Thomas et al. (1982) (Nancy family)

a

3

6

Karges et al. (2005)

2.8

3

Claus et al. (2005) (Leipzig-2 family) Alberti et al. (2001)

2.5–2.9a

2

2

3

Nishihara et al. (2007)

2.5

6

Schwab et al. (1997)

4.2a

3

Two members were euthyroid Prominent eyes

Prematurity (33 and 30 w), LBW (1750, 750 g), Advanced bone age (5.8 at 3 y and 8 y at 5.5 y) gastro-oesophagal with subclinical hyperthyroidism – 1 Patient with subclinical hyperthyroidism 2 Members with subclinical hyperthyroidism Advanced bone age (corresponding to 5.5 y at 4 y) –

127

3 Members with subclinical hyperthyroidism LBW, hyperbillurubinemia, advanced bone age (corresponding to 1 age at 1 y)

H.I. Gozu et al. / Molecular and Cellular Endocrinology 322 (2010) 125–134

M453T ATG → ACG

Treatment with

3

5

2.6

2.2

Tonacchera et al. (1996) (Belfort family) Duprez et al., 1994 (Reims family)

–

1 4.8–5a Khoo et al. (1999)

P639S CCA → TCA N650Y AAC → TAC C672Y TGT → TAT

Mitral valve prolapse, mild proptosis –

4 7 Nwosu et al. (2006) F631S TTC → TCC

Abbreviations: G, DG, NG, MNG: goiter, diffuse goiter, nodular goiter, multinodular goiter, respectively; w: week or weeks; y: year or years; m: months; LBW: low birth weight; SVT: supraventricular tachycardia; n.d.: no data. ␦ the mutant nucleotide and aminoacid sequences were described according to the recommendations for a Nomenclature System for Human Gene Mutations which is described by Antonarakis (2002). a Functional characteristics of these germline mutations were not described in those studies or additional functional data for these mutations were described in other studies. So the data; describing the functional characteristics of these mutations were obtained from the another studies described in http://innere.uniklinikum-leipzig.de/tsh/ and http://www.ssfa-gphr.de/main/ssfa.php (Kleinau et al., 2007).

+ + 18 m to 53 y

+

− + 14–23 y

+

− + 5–38 y

+

+ − 10–42 y

+

+ + + + + + 2 2 2.1–6.5a Jäschke et al. (2010) Führer et al. (1997) (Leipzig family)

Prematurity (33 w), craniosynostosis, advanced bone age and thyroid storm Proptosis in index patient prematurity (30 w), cerebral palsy in 1 patient

No goiter reported DG in 1 (2 y), DG in 1 in early childhood MNG at 18 y) DG in 2 (42 and 19 y), MNG (11 y) and no goiter in the other member DG in 3 (5 y 6 m, 5 y 8 m, 10 y) DG in 2 (14, 23 y), MNG in 1 DG in 5 (18 m, <10 y, <10 y, 19 y, 53 y)

0.5–10 y Neonatal-early childhood

+ + 5 3.5 Ringkananont et al. (2006)

M626I ATG → ATC ATG → ATA L629F TTG → TTT

–

DG in 1 (15 m)

Neonatal-30 y

Surgery ATD

Treatment with Age of diagnosis for hyperthyroidism

Presence of goiter (age of diagnosis; y, m or w) (G, DG, MNG) Additional features Individuals with mutation Basal cAMP fold over wild type TSHR (wt = 1) Reference Mutation

Table 1 (Continued )

−

H.I. Gozu et al. / Molecular and Cellular Endocrinology 322 (2010) 125–134

RadI

128

diagnosed in the mother at the age of 3 years with diffuse goiter (DG). Her second son showed hyperthyroidism at 3.5 weeks of life. Low birth weight and hyperbilirubinemia were the other clinical signs of hyperthyroidism in this patient. Although onset of hyperthyroidism was early and severe in the neonates of these two families, antithyroid drug therapy was successful in controlling hyperthyroidism, but subtotal thyroidectomy and/or radioiodine treatment were performed in the other family members because of recurrent hyperthyroidism. The goiters are generally diffuse in children and tend to become 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 et al., 2005, all described in http://innere.uniklinikum-leipzig.de/tsh, see also Table 1). Diffuse goiter was reported in 59 out of 90 patients with germline TSH receptor mutations in familial non-autoimmune hyperthyroidism. 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-autoimmune hyperthyroidism showed multinodular goiter later in life. Apart from this, goiter is not a consistent manifestation of FNAH. Goiter was not detected in 23 of 90 examined patients with familial non-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, thyroidectomy or radioiodine treatments are frequent in inherited non-autoimmune hyperthyroidism. Radioiodine treatment was administrated in ten families because of multiple relapses of hyperthyroidism after antithyroid drug treatment and/or thyroid surgeries (Thomas et al., 1982; Horton and Scazziga, 1987; Duprez et 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 after radioiodine treatment was also reported for one patient (Horton and Scazziga, 1987). Thyrotoxicosis involves in many of the organ systems including neuropsychiatric manifestations, neuromuscular, cardiovascular, skeletal, gastrointestinal and reproductive systems. Various clinical manifestations have been described in different families such as morning stiffness and pain in the lower limbs (Elgadi et al., 2005), cerebral palsy (Nwosu et al., 2006), hyperactive behavior, sleeping difficulties and enuresis (Biebermann et al., 2001), motor and speech delay (Supornsilchai et al., 2009), supraventricular tachycardia (Elgadi et al., 2005) and mitral valve prolapse (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, ventriculomegaly and scaphocephaly (Supornsilchai et al., 2009), craniosynostosis (Führer et al., 1997), hepatosplenomegaly, jaundice (Supornsilchai et al., 2009) and hyperbiluribinemia (Schwab et al., 1997), prematurity (Führer et al., 1997; Vaidya et al., 2004; Nwosu et al., 2006) and low 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 wild type TSHR (see Table 1). Theoretically the level of constitutive activity of a TSHR mutation might influence the phenotype of disease. A low SCA activity of a germline mutation could require a longer time to induce thyrotoxicosis than mutations with a more pronounced activity. No genotype–phenotype relationship has been reported in patients with germline TSHR mutations. Lower constitutive activity did not consistently correlate with later onset of hyperthyroidism for sporadic TSHR mutations (Lüblinghoff et al., 2009). This is also true for familial TSHR

Table 2 Clinical characteristics of the 14 subjects with 10 different sporadic non-autoimmune hyperthyroidism. Mutation

S281N AGC → AAC

Author

Gruters et al. (1998)

Basal cAMP fold over basal cAMP of wt TSHR (wt = 1)

Premature +/− (w)

3.5

+ (36 w)

− (2520 g)

4m

+ (34 w)

− (2350)

4m

Chester et al. (2008)

Age of diagnosis of hyperthyroidism

Borgel et al. (2005)

6.4*

− (37 w)

− (2550 g)

Neonatal

de Roux et al. (1996)

7

+ (32.5 w)

− (1690 g)

Neonatal

+ (36 w)

− (3040 g)

8m

Lavard et al. (1999)

Holzapfel et al. (1997)

4–5

− (38 w)

+ (2600 g)

5m

Führer et al. (1999)

5*

− (40 w)

+ (2540 g)

11 m

L512Q CTG → CAG

Nishihara et al. (2006)

5

+ (32 w)

− (1860 g)

Neonatal

I568T ATC → ACC

Tonacchera et al. (2000)

5.2

+ (35 w)

+ (2050 g)

5.5 w

+ (35 w)

− (2557 g)

Neonatal

− (37 w)

− (2500 g)

9m

S505N AGC → AAC

Watkins et al. (2008)

V597L GTC → TTC

Esapa et al. (1999)

2.4

Consequences of neonatal hyperthyroidism

Presence of goiter (age of diagnosis) (G, DG, MNG, NG)

ATD

Surgery

Rad I

Craniosynostosis, premature birth, staring eyes Tachycardia, tachypnea, craniosynostosis, advanced bone age, midface hypolasia, dolichocephaly, laryngomalacia and staring eyes –

No goiter

+

+

−

DG (4 m)

+

−

−

G (4.5 y)

+

−

−

Advanced bone age, hepatosplenomegaly, jaundice, premature birth, thrombocytopenic purpura, proptosis, stare and eyelid retraction Advanced bone age, delayed pubertal and psychomotorical development, mental retardation, premature birth, splenomegaly, proptosis, staring eyes Advanced bone age, craniosynostosis, growth retardation, mental retardation, proptosis Advanced bone age, atopic dermatitis, growth retardation, low birth weight Advanced bone age (5 y at 5 m), craniosynostosis (surgery for craniosynostosis), internal hydrocephalus, mental retardation, premature birth, very large goiter Advanced bone age, accelerated statural growth, premature birth, speech disturbance and stare/eye lid retraction, mental retardation Meconium aspiration, pneumothorax, hepatomegaly, sleep difficulties, hyperactivity, advanced bone age Advanced bone age (corresponding 4 y at 10 m, low weight at 9 m (<4th percentile)

DG in neonate

+

−

−

MNG (7 y)

+

+

+

DG (15 m)

+

+

−

DG (4.5 y)

+

−

−

DG (20 y)

+

−

+

DG (5.5 w)

+

−

−

No goiter

+

−

−

DG (9 m)

+

+

−

Treatment with

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A428V GCT → GTT M453T ATG → ACG

LBW +/− (g)

129

− (2400 g) + (36 w)

3.7–5.0* Kopp et al. (1997)

Bircan et al. (2008)

T632I ACC → ATC

D633Y GAC → TAC

4*

5–6 Kopp et al. (1995) F631L TTC → CTC

Abbreviations: G, DG, NG, MNG: goiter, diffuse goiter, nodular goiter, multinodular goiter, respectively; w: week or weeks; y: year or years; m: months; LBW: low birth weight; SVT: supraventricular tachycardia; n.d.: no data. ␦ the mutant nucleotide and aminoacid sequences were described according to the recommendations for a Nomenclature System for Human Gene Mutations which is described by Antonarakis (2002). * Functional characteristics of these germline mutations were not described in those studies or additional functional data for these mutations were described in other studies. So the data; describing the functional characteristics of these mutations were obtained from the another studies described in http://innere.uniklinikum-leipzig.de/tsh/and http://www.ssfa-gphr.de/main/ssfa.php (Kleinau et al., 2007).

− + +

+ (1450 g) + (33 w)

6m

− (1660 g) + (32 w)

Neonatal

Hyperactivity, mental retardation, premature birth, advanced bone age Low birth weight, mental retardation, premature birth, possible cerebral dysgenesis/atrophy, craniosynostosis, mild proptosis Arachnodactyly, craniosynostosis dolichocephaly, hepatomegaly, hypertelorism, Marfan’s syndrome, premature birth, perodactly, proptosis, periorbital edema, advanced bone age (4 y at 6 m) Neonatal

DG (6 m)

+ + MNG (3 y)

+

+

Surgery

+

ATD

DG in neonate, MNG (8 y)

Treatment with

Presence of goiter (age of diagnosis) (G, DG, MNG, NG) Consequences of neonatal hyperthyroidism Age of diagnosis of hyperthyroidism LBW +/− (g) Premature +/− (w) Basal cAMP fold over basal cAMP of wt TSHR (wt = 1) Author Mutation

Table 2 (Continued )

+

H.I. Gozu et al. / Molecular and Cellular Endocrinology 322 (2010) 125–134

Rad I

130

mutations. Hyperthyroidism can begin during the neonatal period although the increase of basal cAMP was low (e.g. a 4-fold basal cAMP increase for A623V was associated with early onset of HT from the neonatal period to 3 years; Schwab et al., 1997). Likewise higher basal cAMP accumulation was not consistently associated with earlier onset of disease. Basal cAMP accumulation of S505N (5-fold) and P639S (5-fold) were high, but the age of onset of hyperthyroidism was at 19 months to 9 years (Vaidya et al., 2004) and 5–38 years (Khoo et al., 1999) in these patients, respectively. Moreover the patients of the same family carrying the same TSHR germline mutation showed large differences in the onset and/or severity of the disease (Arturi et al., 2002; Vaidya et al., 2004; Thomas et al., 1982 for M463V, S505N and V509A, respectively). Similarly, various phenotypes were also identified in the different 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; Elgadi et al., 2005; Karges et al., 2005; Pohlenz et al., 2006; Ferrara et al., 2007). Except from the absence of clinical signs of thyroid autoimmunity, the presence of a positive family history for non-autoimmune hyperthyroidism and the presence of an active clinical course with multiple relapses of hyperthyroidism under antithyroid medication and even after radioiodine therapy and/or non-total thyroidectomy for the majority of the patients, no specific clinical features can be described for patients with FNAH. The fact that no direct relation of the in vitro activity of the TSHR mutation (basal cAMP value) and the age at onset of HT and the severity of clinical course was found and that even for the same TSHR mutation different clinical courses in different families were described suggests that the clinical course is more likely influenced by further genetic/epigenetic and environmental factors than by the in vitro activity of the TSHR mutation itself. 4. Clinical hallmarks of sporadic non-autoimmune hyperthyroidism Clinical characteristics of the subjects with sporadic nonautoimmune hyperthyroidism are described in Tables 2 and 3 (see also http://innere.uniklinikum-leipzig.de/tsh/for further details). 5. Sporadic non-autoimmune hyperthyroidism is more severe than familial autosomal dominant hyperthyroidism The family history for non-autoimmune hyperthyroidism is negative in sporadic non-autoimmune hyperthyroidism. The phenotype of a patient with congenital sporadic hyperthyroidism was first described by Kopp et al. (1995). A thymidine to cytosine (T to C position) transition causing the substitution of leucine (CTC) for phenylalanine (TTC) at position 631 in one allele was identified in the DNA from the patient’s leucocytes and nodular thyroid tissue. This mutation could not be detected in the patient’s parents and sister, showing that the patient had a de novo germline mutation. Stigmata of autoimmunity and lymphocytic infiltration in the thyroid gland are absent in sporadic non-autoimmune hyperthyroidism. Endocrine ophthalmopathy as an extraocular finding of autoimmune hyperthyroidism has not been described in sporadic non-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 eyelid retraction may be caused by congenital thyrotoxicosis (de Roux et al., 1996; Gruters et al., 1998; Lavard et al., 1999; Tonacchera et al., 2000; Chester et al., 2008). Onset of disease is earlier (neonatal period to 11 months) and more severe than hereditary non-autoimmune hyperthyroidism.

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Fig. 1. Localizations of the inherited/sporadic germline TSHR mutations. Most of the inherited TSHR mutations are located in first, second, third and fifth tramsmembrane segment but several inherited germline tshr mutations are located in first and second extracellular loop of the receptor. Besides the inherited germline TSHR mutations; sporadic germline mutations also mostly located in first, second, third and fifth transmembrane segment with a few exceptions. Some of the sporadic germline TSHR mutations located in extracellular domain and second extra cellular loop of the receptor.

Patients with SNAH frequently presented with fetal or neonatal onset of hyperthyroidism (10 instead of 5 patients in FNAH). Congenital sporadic hyperthyroidism can be very severe thus requiring prompt initial treatment in an intensive care unit (ICU) (Kopp et al., 1997). Exceptionally, also a very mild course of hyperthyroidism has been reported for SNAH. The patient showed no consequences of neonatal hyperthyroidism. Antithyroid treatment was successful in controlling hyperthyroidism for the first 5.9 years of age (Borgel et al., 2005). The thyroid size of patients with sporadic non-autoimmune hyperthyroidism is also variable. Nine of 14 patients presented a diffuse goiter at disease onset (see Table 2). With longer duration of the disease the diffuse goiter usually turns into a multinodular goiter (Kopp et al., 1995). Only two cases reported a nodular goiter at first onset at 3 and 7 years, respectively (Kopp et al., 1997; Lavard et al., 1999). Moreover, a large thyroid volume of 370 ml at 20 years was revealed by CT of the neck in one case (Nishihara et al., 2006). No goiter was reported in two cases with congenital sporadic hyperthyroidism (Gruters et al., 1998; Watkins et al., 2008; see Tables 2 and 3). Hyperthyroidism commonly relapses following withdrawal of antithyroid drugs and also after subtotal thyroidectomy. Therefore, not only early diagnosis is important in congenital hyperthyroidism, but also combined ablative regimens should be considered. Early combined treatment with near-total thyroidectomy plus radioiodine therapy have been reported to be the treatment of choice for some patients with sporadic non-autoimmune hyperthyroidism (Kopp et al., 1995, 1997; Lavard et al., 1999). Moreover radioiodine therapy was administrated four times from the age 9–13 years in the patient reported by Lavard et al. (1999). Various consequences of prolonged neonatal hyperthyroidism including goiter, microcephaly, craniosynostosis, psychomotor disturbances, mental retardation, intrauterine growth retardation, prematurity, low birth weight, proptosis, stare, eyelid retraction and advanced bone age have been reported.

In contrast to FNAH, the majority of the patients with sporadic NAH were prematurely born (10 of 14 patients) and some presented with low birth weight (4 of 14 patients) (see Tables 2 and 3). Early and effective control of hyperthyroidism in these children with an activating TSHR mutation is essential to prevent permanent psychomotor retardation, advanced bone age and craniosynostosis and it’s complications as it is seen frequently in patients with SNAH (see Tables 2 and 3). The germline mutations that caused congenital hyperthyroidism were heterozygous and affected only one allele. However, also cases with a silent TSHR germline polymorphism (not displaying constitutive activity in vitro) were described for two patients with hyperthyroidism and with additional sporadic or somatic TSHR mutations, respectively. Gruters et al. (1998) identified a S281N sporadic germline mutation, thus explaining the severe congenital hyperthyroidism in this patient. Additionally, the silent polymorphism R528H. was detected in the index patient and in four additional family members. Moreover, Gozu et al. (2008) reported a silent germline mutation (N372T) together with the constitutively active somatic TSHR mutation S281N in a hot thyroid nodule. Congenital sporadic hyperthyroidism should be distinguished from the more common familial autosomal dominant NAH in order not to miss timely therapy in genetically diagnosed family members and because of earlier onset of disease (neonatal period to 11 months) and more severe clinical courses of SNAH than hereditary NAH, causing irreversible consequences if untreated (Kopp et al., 1995). Patients with SNAH were frequently presented with complications of fetal/neonatal hyperthyroidism like prematurity (10 instead of 4 patients in FNAH), craniosynostosis (6 instead of 2 patients in FNAH), mental retardation (6 instead of 2 patients in FNAH), advanced bone age (11 instead of 7 patients in FNAH), frequent relapses of hyperthyroidism after antithyroid drugs, thyroid surgery and radioiodine therapy (8 patients in SNAH). Patients with familial NAH show milder clinical courses of hyperthyroidism often controlled with antithyroid drugs and there are even family mem-

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Table 3 Association of clinical signs of sporadic non-autoimmune hyperthyroidism with the LRA, modified according to Lüblinghoff et al. (2009). Clinical sign

Total number of patients with respective clinical sign

Number of patients with low in vitro activity: LRA < 15.1 (total number n = 6)

Number of patients with high in vitro activity: LRA ≥ 15.1 (total number n = 8)

Onset of HT Fetal Neonatal late (>1 month)

3 7 4

3 2 1

0 5 3

Goiter Age at onset of goiter ≤1 month ≤15 months >15 months

2 5 5

1 1 4

1a 4a 1a

4 2 3d

5 0 0a

4 4 3 3 5

6 2 3 1 6

0d 2d 3d 4

4 1 3 4

Morphology of goiter at onset of goitera , b DG 9 MNG 2 3 Excessive growthc Prematurity Mental retardation Craniosynostosis Low birth weight (<10th percentile) Advanced bone age Duration of HT (in years) ≤1 1 < HT ≤ 3 HT > 3 Active clinical coursee

10 6 6 4 11

4 3 6 8

a

No goiter reported by Gruters et al. (1998) and Watkins et al. (2008). 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 at 20 years; Holzapfel et al. (1997): 16 ml at 25 months; Führer et al. (1999): 48 ml at 12.3 years. d No follow-up data for de Roux et al. (1996). e Frequent relapses of HT under antithyroid drug therapy, thyroid surgery and/or radioiodine therapy plus complications of sporadic non-autoimmune HT such as prematurity, low birth weight, advanced bone age and mental retardation were characteristics of an active clinical course. b

bers with subclinical hyperthyroidism or euthyroidism (9 patients in FNAH). Functional analysis of the de novo sporadic TSHR mutations showed that basal cAMP accumulation of these mutations range from 2.4 (V597L) to 7 (M453T)-fold increase of basal cAMP compared with the wt TSHR (see Table 2). Patients with the same sporadic TSHR mutations showed completely different clinical courses. A milder clinical course was described by de Roux et al. (1996), Führer et al. (1999), and Tonacchera et al. (2000), whereas Lavard et al. (1999), Holzapfel et al. (1997) and Watkins et al. (2008) reported a severe clinical course with frequent relapses of hyperthyroidism for patients with M453T, S505N and I568T, respectively (Lüblinghoff et al., 2009). For better understanding of the constitutive activity of the TSHR, linear regression analysis (LRA) of constitutive activity as a function of the TSHR expression was described as a more reliable way to characterize the in vitro activity of a constitutively active TSHR mutation compared to the basal cAMP levels (Müller et al., 2009). No consistent relation of the LRA values of the sporadic TSHR mutations and the clinical signs of patients with sporadic NAH was described (Lüblinghoff et al., 2009). Although high LRA values were found for some sporadic TSHR mutations (25.6 for I568T and 45.9 for F631L), these patients did not show an active clinical course compared to patients for which lower LRA values of the TSHR mutations were described (M453T with 5.2 and L512Q with 4.5). A mild clinical course with neonatal onset of hyperthyroidism was controlled with antithyroid drugs associated with a I568T mutation (Tonacchera et al., 2000). de Roux et al. (1996) and Lavard et al. (1999) reported two unrelated patients with the TSHR mutation M453T. Although the LRA of this mutation was very low (with 5.2), both patients showed the fetal onset of hyperthyroidism and were delivered before term. They might be classified

as active clinical course. For the patients described by de Roux et al. (1996), euthyroidism could be easly achieved with antithyroid drugs. But medical treatment and subtotal thyroidectomy could not stop relapses of hyperthyroidism, so repeated ablative radioiodine therapy was necessary on a patient with severe hyperthyroidism reported by Lavard et al. (1999). No clear evidence was diagnosed for a consistent relation of the TSHR mutation’s in vitro activity determined by LRA with the clinical course of patients with SNAH. Moreover, the comparison of the clinical courses of the patients harboring the same mutation also show no relation of the clinical activity with a high LRA. This was most likely due to different diagnostic circumstances and therapeutic strategies, limitations of a systemic analysis of case reports due to limited follow-up and the restricted case number of 14 patients. This may be also due to action of genetic, epigenetic and environmental modifiers like iodine supply (Lüblinghoff et al., 2009). Furthermore, a more detailed analysis of all published case reports did also not show any association of in vitro activities determined by LRA and several clinical indicators of hyperthyroidism activity (Table 3, modified according to Lüblinghoff et al., 2009). However, the comparison of the median LRA values of all 14 published sporadic TSHR mutations with the 17 published LRA values of 24 familial TSHR mutations did show a significantly higher median LRA for sporadic as compared to familial autosomal dominant hyperthyroidism (Lüblinghoff et al., submitted for publication). This finding is in line with the clinical impression of a more active clinical course in patients with sporadic NAH with earlier onset of HT, severe complications of HT such as craniosynostosis and mental retardation and an active clinical course with relapses of HT even after radioiodine therapy and/or thyroid surgery compared to the clinical course of patients with familial NAH. Furthermore, because of the low in vitro activity of the familial TSHR mutation the thy-

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roid tissue in patients with FNAH needs to reach a certain volume to affect the patients’ phenotype thus explaining the later onset of HT in patients with FNAH compared to those with SNAH. Moreover, a high in vitro activity of a familial TSHR mutation could very likely lead to a more severe survival disadvantage and thus would be less likely inherited by the next generation whereas the sporadic TSHR germline mutations occur as de novo mutations. Thus their manifestation in the first generation is not affected by a similar negative genetic selection. There are several possible explanations for the differences found between TSHR genotype and clinical phenotype. G protein receptor kinase2 (GRK2) and ␤-arrestin 1 are negative regulators of thyrotropin receptor-stimulated response (Iacovelli et al., 1996). GPRKs belong to a family of serine-threonine kinases which phosphorylate the agonist form of GPCR. The phosphorylated GPCR binds to a second family of proteins, termed ␤-arrestin leading to receptor uncoupling and signal shut off (Penela et al., 2001; Voigt et al., 2004). ␤-Arrestin-induced desensitization and downregulation of the receptor is one of the possible explanations for this discrepancy. In line with this reasoning is the increased expression of ␤-arrestin 2 that has been found in hot nodules (Voigt et al., 2000). Moreover, variations in other signaling molecules like PDEs, G-proteins, GRAPs, Adenylate cyclases, CREM, CREB, etc. are further possible explanations. Moreover, most likely additional factors like the genetic back ground and/or iodine intake may modify the phenotypic expression (Trulzsch et al., 2001; Gozu et al., 2009a,b). In conclusion, a rare form of persistent hyperthyroidism is caused by germline mutations in the TSH receptor in the absence of maternal autoimmunity. Germline-activating TSHR mutations cause sporadic congenital hyperthyroidism or non-autoimmune familial hyperthyroidism presenting with mild to severe clinical courses of hyperthyroidism. No genotype–phenotype relations has been reported in patients with germline TSHR mutations. This might be the effect of other genetic, epigenetic and environmental factors. Delayed or inadequate treatment may aggravate developmental abnormalities due to hyperthyroidism in these children. Therefore, early recognition of such cases is important and appropriate treatment and early diagnosis of the other family members is necessary. References Alberti, L., Proverbio, M.C., Costagliola, S., Weber, G., Beck-Peccoz, P., Chiumello, G., Persani, L., 2001. A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism. Eur. J. Endocrinol. 145 (3), 249–254. Allgeier, A., Offermanns, S., Van Sande, J., Spicher, K., Schultz, G., Dumont, J.E., 1994. The human thyrotropin receptor activates G-proteins Gs and Gq/11. J. Biol. Chem. 269 (19), 13733–13735. Akcurin, S., Turkkahraman, D., Tysoe, C., Ellard, S., De Leener, A., Vassart, G., Costagliola, S., 2008. A family with a novel TSH receptor activating germline mutation (p.Ala485Val). Eur. J. Pediatr. 167, 1231–1237. Antonarakis, S.E., The Nomenclature Working Group, 2002. Recommendations for a nomenclature system for human gene mutations. Hum. Mutat. 11, 1–3. Arturi, F., Chiefari, E., Tumino, S., Russo, D., Squatrito, S., Chazenbalk, G., Persani, L., Rapoport, B., Filetti, S., 2002. Similarities and differences in the phenotype of members of an Italian family with hereditary non-autoimmune hyperthyroidism associated with an activating TSH receptor germline mutation. J. Endocrinol. Invest. 25, 696–701. Biebermann, H., Schoneberg, T., Hess, C., Germak, J., Gudermann, T., Gruters, A., 2001. The first activating TSH receptor mutation in transmembrane domain 1 identified in a family with nonautoimmune hyperthyroidism. J. Clin. Endocrinol. Metab. 86, 4429–4433. Bircan, R., Miehle, K., Mladenova, G., Ivanova, R., Sarafova, A., Borissova, A.M., Lüblinghoff, J., Paschke, R., 2008. Multiple relapses of hyperthyroidism after thyroid surgeries in a patient with long term follow-up of sporadic non-autoimmune hyperthyroidism. Exp. Clin. Endocrinol. Diabetes 116 (6), 341–346. Borgel, K., Pohlenz, J., Koch, H.G., Bramswig, J.H., 2005. Long term carbimazole treatment of neonatal nonautoimmune hyperthyroidism due to a new activating TSH receptor gene mutation (Ala428Val). Horm. Res. 64, 203–208. Chester, J., Rotenstein, D., Ringkananont, U., Steuer, G., Carlin, B., Stewart, L., Grasberger, H., Refetoff, S., 2008. Congenital neonatal hyperthyroidism caused by

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