Sporadic Nonautoimmune Hyperthyroidism Research Articles

A Case of Definitive Therapy in Persistent Congenital Hyperthyroidism Secondary to an Activating Variant of the TSHR Gene

Background: Sporadic congenital non-autoimmune hyperthyroidism (SCNAH) causes permanent hyperthyroidism secondary to activating mutations in the TSHR gene. SCNAH usually presents during infancy and can be difficult to treat with antithyroid drugs or subtotal thyroidectomy.1 When adequate therapy is delayed, irreversible sequela such as craniosynostosis, growth failure, and cognitive delays may develop. Definitive therapy for children with SCNAH is recommended with no consensus on timing or type of intervention. Our case highlights the importance of early total thyroidectomy to optimize clinical outcomes in patients with SCNAH.Clinical case: A now 3-year-old male was born small for gestational age (SGA) at 34 weeks gestation with biochemical and clinical signs of hyperthyroidism in the neonatal period. On day of life 6, his TSH was 0.02 mcU/mL (reference range 0.34-5.6 mcU/mL) and free thyroxine (T4) was 5.42 ng/dL (reference range 0.58-1.64 ng/dL). Methimazole (MMI) 0.3 mg/kg/day was started at that time, and the dose was titrated over 6 weeks of life to 0.8 mg/kg/day due to continued elevation of free T4 levels. Negative thyroid autoantibodies and normal maternal thyroid studies prompted genetic testing at 3 months of age. This testing revealed a heterozygous variant in the TSHR gene [c.842G->A (p.G116R)] that was determined to be pathologic. Despite frequent MMI dose changes and confirmation of medication adherence, high-dose MMI was not effective in consistently normalizing his TSH and free T4 levels in the first two years of life. Concerns for poor growth and hyperactive behavior were also present. A “block and replace” strategy was not feasible since the patient remained hyperthyroid even at MMI doses up to 0.8 mg/kg/day. Despite normal insulin-like growth factor 1 and insulin-like growth factor binding protein 3 levels, poor linear growth persisted with a height Z-score of -3.61 by age 3 years. While he was SGA at birth, his recurrent hyperthyroidism impeded catch-up growth potential, so treatment with growth hormone (rhGH) was initiated. His height Z-score improved to -2.39 after 9 months on rhGH dosed at 0.18 mg/kg/week. Due to the difficulty in consistently managing him medically with MMI, he underwent total thyroidectomy at age three.Conclusion: There is currently no consensus on the timing of definitive therapy for children with SCNAH. This case highlights the importance of considering total thyroidectomy at an early age to avoid long-term sequela of persistent hyperthyroidism.1. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010;322:125–34.

Advanced Bone Age Present in a Neonatal Case of Sporadic Non-Autoimmune Hyperthyroidism Before Onset of Symptoms

Advanced Bone Age Present in a Neonatal Case of Sporadic Non-Autoimmune Hyperthyroidism Before Onset of Symptoms

Long-Term Follow-Up of a Patient with Sporadic Nonautoimmune Hyperthyroidism Due to a Thyrotropin-Receptor Mutation (D619G)

ABSTRACT Objective: Sporadic nonautoimmune hyperthyroidism caused by germline mutations of the thyrotropin receptor (TSHR) gene is a very rare disease that manifests as severe congenital hyperthyroidism. We describe a case presenting with sporadic nonautoimmune hyperthyroidism during adolescence. Methods: Laboratory data, imaging, histopathology, clinical follow-up, and DNA sequencing were evaluated. Results: The patient was born at term with a normal birth weight but showed increased growth velocity at approximately 7 months. He had no medical consultation before tachycardia was detected at a school physical examination at the age of 13 years. Thyroid function tests confirmed hyperthyroidism with negative anti-TSHR antibodies. After maintaining methimazole therapy for 12 years, he underwent total thyroidectomy, and the weight of the resected thyroid tissue was 131 g. The subsequent histopathologic findings showed an encapsulated follicular adenoma, adenomatous goiter, and hyperplastic changes of the foll...

Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism.

Primary nonautoimmune hyperthyroidism is a rare cause of neonatal hyperthyroidism. This results from an activating mutation in the thyrotropin-receptor (TSHR). It can be inherited in an autosomal dominant manner or occur sporadically as a de novo mutation. Affected individuals display a wide phenotype from severe neonatal to mild subclinical hyperthyroidism. We describe a 6-month-old boy with a de novo mutation in the TSHR gene who presented with accelerated growth, enlarging head circumference, tremor and thyrotoxicosis. Genomic DNA from the patient's and parents' peripheral blood leukocytes was extracted. Exons 9 and 10 of the TSHR gene were amplified by PCR and sequenced. Sequencing exon 10 of the TSHR gene revealed a novel heterozygous missense mutation substituting cytosine to adenine at nucleotide position 1534 in the patient's peripheral blood leukocytes. This leads to a substitution of leucine to methionine at amino acid position 512. The mutation was absent in the parents. In silico modeling by PolyPhen-2 and SIFT predicted the mutation to be deleterious. The p.Leu512Met mutation (c.1534C>A) of the TSHR gene has not been previously described in germline or somatic mutations. This case presentation highlights the possibility of mild thyrotoxicosis in affected individuals and contributes to the understanding of sporadic non-autoimmune primary hyperthyroidism.

2012 European Thyroid Association Guidelines for the management of familial and persistant sporadic non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations

2012 European Thyroid Association Guidelines for the management of familial and persistant sporadic non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations

Non-autoimmune hyperthyroidism caused by thyroid-stimulating hormone receptor germline mutations - 2012 European Thyroid Association Guidelines

All cases of familial thyrotoxicosis with absence of evidence of autoimmunity and all children with persistent isolated neonatal hyperthyroidism should be evaluated for familial non-autoimmune autosomal dominant hyperthyroidism (FNAH) or persistent sporadic non-autoimmune hyperthyroidism (PSNAH). First, all index patients should be analysed for the presence/absence of a thyroid-stimulating hormone (TSH) receptor (TSHR) germline mutation, and if they display a TSHR germline mutation, all other family members including asymptomatic and euthyroid family members should also be analysed. A functional characterization of all new TSHR mutations is necessary. Appropriate ablative therapy is recommended to avoid relapses of hyperthyroidism and its consequences, especially in children. Therefore, in children the diagnosis of FNAH or PSNAH needs to be established as early as possible in the presence of the clinical hallmarks of the disease.

Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene

Germline mutations of thyrotropin receptor (TSHR) gene determining a constitutive activation of the receptor were identified as a molecular cause of familial or sporadic congenital nonautoimmune hyperthyroidism (OMIM: 609152) (Nat Genet 7:396-401, 1994; N Engl J Med 332:150-154, 1995; Acta Endocrinol (Copenh) 100:512-518, 1982). We report the case of an Italian child subjected to the first clinical investigation at 24months for an increased growth velocity; biochemical investigation showed high FT4 and FT3 serum values and undetectable thyrotropin in the absence of anti-thyroid antibodies; the thyroid gland was normal at ultrasound examination. Treatment with methimazole was started at the age of 30months when her growth velocity was high and the bone age was advanced. DNA was extracted from her parents', brother's, and the patient's blood. Exons 9 and 10 of the TSHR gene were amplified by polymerase chain reaction and subjected to direct sequencing. In proband, a heterozygous substitution of cytosine to thymine determining a proline to serine change at position 639 (P639S) of the TSHR was detected while the parents and brothers of the propositus, all euthyroid, showed only the wild-type sequence of the TSHR gene. This mutation was previously described as somatic in patients affected by hyperfunctioning thyroid nodules and as germline in a single Chinese family affected by thyrotoxicosis and mitral valve prolapse. This constitutively activating mutation is able to activate both the cyclic AMP and the inositol phosphate metabolic pathways when expressed in a heterologous system. In conclusion, we describe the first case of sporadic congenital nonautoimmune hyperthyroidism caused by de novo germinal P639S mutation of TSHR.

TSH receptor extracellular region mutations in thyroid functioning nodules: further evidence for the functional role of this region in the receptor activation

IntroductionA causative role for activating mutations of the TSHreceptor (TSHR) has been demonstrated in the majority ofthyroid hyperfunctioning nodules, as well as for thefamilial and sporadic congenital nonautoimmune hyper-thyroidism [1, 2] and also the rare hyperfunctioning car-cinomas [3, 4]. More than 30 different amino acidsubstitutions have been described so far, and their char-acterization, together with in vitro mutagenesis studieshave been exploited for a structure–function analysis of thereceptor, leading to a structural model in which the areasinvolved in the binding to TSH or signal transduction havebeen depicted [5]. The emerging picture suggests theexistence of a molecular constraint which limits the con-stitutive activity of the receptor, removed by the interactionof TSH with the extracellular (EX) portion, but with animportant role played also by the transmembrane regions inthe dimerization process and the functional activation ofthe receptor [5, 6]. Herein we describe the discovery of twounusual heterozygous mutations occurring in two of seventhyroid functioning nodules detected as single nodules or ina multinodular goiter.Materials and methodsSpecimen of nodular tissues were collected and immedi-ately frozen after surgical removal from seven patients withsingle or multinodular hyperfunctioning goiter. Non-nod-ular normal tissue from the contralateral lobe was alsocollected. After RNA extraction and cDNA synthesis, PCRamplification of the exons 9 and 10 of the TSHR gene wasperformed as previously described [3, 4] and the amplifiedproducts sequenced with a BigDye Terminator version 3.1Cycle Sequencing kit in an automated 3130xl analyzer(both from Applied Biosystems, Foster City, CA, USA).The study protocol was approved by the local ethicscommittee.ResultsSequencing of TSH receptor gene in a small cohort ofseven patients with thyroid hyperfunctioning nodulesrevealed the presence, in two cases, of unusual somaticheterozygous mutations. The first was a deletion of D403

Hyperthyroidism Caused by a Germline Activating Mutation of the Thyrotropin Receptor Gene: Difficulties in Diagnosis and Therapy

Germline activating mutations of the thyrotropin receptor (TSHR) gene have been considered as the only known cause of sporadic nonautoimmune hyperthyroidism in the pediatric population. Here we describe the long-term follow-up and evaluation of a patient with sporadic nonautoimmune primary hyperthyroidism who was found to have a de novo germline activating mutation of the TSHR gene. The patient was an infant who presented at the age of 10 months in an unconscious state with exsiccation, wet skin, fever, and tachycardia. Nonautoimmune primary hyperthyroidism was diagnosed, and brain magnetic resonance imaging and computed tomography showed also Arnold-Chiari malformation type I. Continuous propylthiouracil treatment resulted in a prolonged clinical cure lasting for 10 years. At the age of 11 years and 5 months the patient underwent subtotal thyroidectomy because of symptoms of trachea compression caused by a progressive multinodular goiter. However, 2 months after surgery, hormonal evaluation indicated recurrent hyperthyroidism and the patient was treated with propylthiouracil during the next 4 years. At the age of 15 years the patient again developed symptoms of trachea compression. Radioiodine treatment resulted in a regression of the recurrent goiter and a permanent cure of hyperthyroidism without relapse during the last 3 years of his follow-up. Sequencing of exon 10 of the TSHR gene showed a de novo heterozygous germline I630L mutation, which has been previously described as activating mutation at somatic level in toxic thyroid nodules. The I630L mutation of the TSHR gene occurs not only at somatic level in toxic thyroid nodules, but also its presence in germline is associated with nonautoimmune primary hyperthyroidism. Our case report demonstrates that in this disorder a continuous growth of the thyroid occurs without any evidence of elevated TSH due to antithyroid drug overdosing. This may justify previous recommendations for early treatment of affected patients with removal of as much thyroid tissue as possible.

Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism

Up to date, 14 patients with sporadic non-autoimmune hyperthyroidism (SNAH) caused by sporadic germline mutations in the TSH receptor (TSHR) gene have been reported. Despite considerable differences in the activity of hyperthyroidism, all SNAH case reports concluded that the demonstrated constitutive activity explains the phenotype. Recently, linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125I-bTSH binding or fluorescence activated cell sorting analysis was described as a more reliable way of characterizing the in vitro activity (IVA) of a constitutively activating TSHR mutation. Therefore, we analyzed a possible genotype-phenotype correlation in a systematic review of the case reports and investigated the TSHR mutation's LRA in selected cases. We determined the LRA for all sporadic germline mutations which had not previously been reported. Moreover, we systematically evaluated all case reports of SNAH for evidence of an association of the clinical course (CC) with the IVA of the mutated TSHR. The LRA determined were: M453T (5.2+/-0.8), L512Q (4.5+/-0.7), I568T (25.6+/-6.3), F631L (45.9+/-9.4), T632I (14.5+/-2.7), D633Y (16.4+/-6.4). None of the 10 examined clinical signs showed a significant association with the LRA. Moreover, the comparison of the CC of patients harboring the same mutation (S281N, M453T, I568T, S505N) also showed no relation of the clinical activity with a high LRA. Considering the different diagnostic circumstances, therapeutic strategies and the limitations of a systematic analysis of case reports due to the restricted number of case reports and limited follow-up we found no consistent relation of the TSHR mutation's IVA determined by LRA with the CC of patients with SNAH. This may also be due to the action of genetic, epigenetic, and environmental modifiers.

Multiple Relapses of Hyperthyroidism after Thyroid Surgeries in a Patient with Long Term Follow-up of Sporadic Non-autoimmune Hyperthyroidism

Constitutively activating thyrotropin receptor (TSHR) germline mutations have been identified as a molecular cause of congenital hyperthyroidism. Patients with relapsing hyperthyroidism were previously treated with surgery and radioiodine. We report on a 22-year-old male patient who was treated for his multiple relapses of hyperthyroidism by repeated subtotal thyroidectomies (STE). During the 22 years of follow-up, the patient developed several relapses of hyperthyroidism, four of them after thyroid surgeries. Sequencing of the TSHR gene revealed a gain-of-function mutation with an amino acid exchange of aspartate to tyrosine in codon 633 which is located in the sixth transmembrane domain of the TSH receptor. The absence of the mutation in all other family members identifies the patient's TSHR mutation as a sporadic germline mutation. In this patient, thyroid tissue growth and hyperthyroidism could repeatedly be controlled only for limited periods by near total thyroidectomy. Therefore, this case confirms that early combined treatment with near-total thyroidectomy plus radioiodine therapy seems to be the treatment of choice for patients with sporadic non-autoimmune hyperthyroidism.

Multiple relapses of hyperthyroidism in a patient with long term follow up of sporadic non-autoimmune hyperthyroidism

We report a male patient with neonatal non autoimmune hyperthyroidism due to an activating thyrotropin receptor (TSHR) germline mutation with multiple relapses despite repeated subtotal thyroidectomy.

Variable Phenotype Associated with Ser505Asn-Activating Thyrotropin-Receptor Germline Mutation

Constitutively activating thyrotropin-receptor (TSHR) germline mutations have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. To date, seven cases of familial and six cases of sporadic nonautoimmune hyperthyroidism have been described associated with 13 different TSHR germline mutations, with a variable clinical course. We report the case of a 12.3-year-old girl with a history of thyrotoxicosis since the age of 11 months who developed diffuse thyroid hyperplasia at the age of 4.5 years. The patient has required continuous moderate-dose antithyroid medication, to maintain euthyroidism. There were no clinical signs of autoimmune thyroid disease and autoantibodies were negative. An activating germline mutation in the TSHR gene was suspected and was found in TSHR exon 10 (Ser505Asn) but was absent in the girl's mother. This same mutation, was first reported in a patient with severe intrauterine hyperthyroidism with early and progressive goiter development. Our patient had a significantly less severe clinical course with later onset compared to the original patient with the same TSHR germline mutation.