A de novo pathogenic variant in TSHR expanding the phenotype of persistent sporadic congenital non-autoimmune hyperthyroidism: a case report and literature review

Introduction

Non-autoimmune hyperthyroidism (NAH) is a rare hereditary disease, which can be divided into two types: familial nonautoimmune autosomal dominant hyperthyroidism (FNAH) and persistent sporadic congenital NAH (PSNAH). The disease is due to thyroid-stimulating hormone receptor (TSHR) germline mutations, causing activation of its function and leading to thyrotoxicosis (1-3). To date, only a limited number of NAH cases have been documented, typically characterized by early-onset hyperthyroidism with multi-system involvement manifesting as exophthalmos, craniosynostosis, accelerated skeletal maturation, and neurodevelopmental delays (2,3). In this study, we report on a 34-month-old boy with PSNAH, who exhibits a severe phenotype characterized by marked mitral valve disease and cerebellar tonsillar herniation—findings that further refine the clinical spectrum of the condition as outlined in the medical literature. A systematic analysis of the patient’s clinical course was performed, complemented by a comprehensive review of the disease’s genetic and clinical spectrum. Through retrospective evaluation of clinical data and integration with existing literature, we elucidate the mechanistic links between prolonged thyrotoxicosis and structural cardiac/neurological complications, emphasizing the critical role of early genetic diagnosis in mitigating end-organ damage. We present this article in accordance with the CARE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-380/rc).

Case presentation

This case report describes a pediatric patient ultimately diagnosed with PSNAH in the Department of Pediatrics at Peking University First Hospital in September 2022. This male patient, aged 34 months, presented to our institution with exertional dyspnea. The child was born via vaginal delivery at 32 weeks of gestation to non-consanguineous Chinese Han parents, with birth parameters within normal ranges [weight 2,000 g (50–90th percentile), length 44 cm (50–90th percentile)].

During neonatal care for prematurity, cranial ultrasound revealed mild ventriculomegaly and echocardiography detected cardiomegaly; however, neither finding prompted further clinical evaluation. Postnatal longitudinal monitoring identified failure to thrive with progressive craniofacial dysmorphic features, including frontal bossing and scaphocephaly, alongside premature anterior fontanelle closure at 6 months. Developmental surveillance documented delayed milestones: independent ambulation was achieved at 15 months, followed by the emergence of a wide-based gait and persistent deficits in hand-eye coordination. At 33 months of age, the patient developed progressive respiratory distress manifesting as tachypnea, exertional fatigue and persistent diaphoresis in the absence of infectious signs. Repeat echocardiography revealed four-chambered cardiac dilation, severe mitral regurgitation, and pulmonary hypertension (PH) (estimated systolic pulmonary artery pressure 65 mmHg). Concurrent cranial magnetic resonance imaging (MRI) delineated significant bilateral ventriculomegaly and cerebellar tonsillar herniation. Initial stabilization involved diuretics and phosphodiesterase-5 inhibitor therapy (sildenafil 3 mg/kg/day), with parallel consultations from pediatric cardiothoracic surgery and neurosurgery teams. The patient was subsequently transferred to our tertiary center for comprehensive multidisciplinary evaluation, prioritizing simultaneous management of cardiac and neurological emergencies.

On admission, physical exam showed afebrile (36.8 °C), marked tachycardia (140 bpm), tachypnea (36 breaths/min), and normotension (104/57 mmHg). Anthropometric measurements revealed significant growth discordance: weight 11.2 kg (<3rd percentile), height 102 cm (75–90th percentile), and head circumference 47 cm (10–25th percentile). Physical examination demonstrated characteristic craniofacial dysmorphism, including dolichocephalic skull configuration with frontal bossing, bilateral proptosis and asthenic habitus. Cardiovascular assessment revealed a hyperdynamic precordial impulse with lateral displacement of the apical beat. Auscultation identified a grade 4/6 holosystolic murmur at the mitral zone, radiating to the left axilla and interscapular region. No hepatomegaly or peripheral edema was observed. Neurological evaluation demonstrated age-appropriate cognitive function but revealed mild gross motor delay with objective balance impairment.

Initial laboratory investigations demonstrated unremarkable hematological and biochemical parameters. Markedly elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP, 4,053 pg/mL, reference range <300 pg/mL) confirmed cardiac decompensation. Imaging studies revealed cardiomegaly (cardiothoracic ratio 0.65, Figure 1A) on chest radiography and echocardiographic evidence of hyperdynamic left ventricular function with chamber dilation, severe mitral regurgitation (Figure 1B), and PH (estimated systolic pulmonary artery pressure 67 mmHg). Neuroimaging identified bilateral ventriculomegaly with tonsillar herniation (Figure 1C). Skeletal maturation was advanced by 5 years.

Figure 1 Imaging findings of the patient. (A) The patient’s chest radiograph demonstrated cardiomegaly with a cardiothoracic ratio of 0.65; (B) the patient’s echocardiography revealed mitral valve deformation accompanied by massive regurgitation; (C) the patient’s cranial MRI revealed ventriculomegaly and tonsillar herniation. MRI, magnetic resonance imaging.

Thyroid function tests confirmed profound thyrotoxicosis: undetectable thyrotropin (TSH, 0.01 µIU/mL), elevated total thyroxine (T4, 288.7 nmol/L), free T4 (73.39 pmol/L), total triiodothyronine (T3, 9.78 nmol/L), and free T3 (>30.8 pmol/L). Autoimmune thyroiditis was excluded through negative thyrotropin receptor antibody (TRAb), antithyroglobulin antibody (TgAb), and thyroid peroxidase antibody (TPOAb), with normal thyroglobulin levels (29.6 µg/L). Thyroid ultrasonography demonstrated diffuse hyperplasia with heterogeneous echotexture. The combination of NAH, craniofacial dysostosis, neurodevelopmental abnormalities, and cardiopulmonary manifestations, alongside normal parental thyroid function and absence of family history, supported a diagnosis of congenital NAH. Graves’ disease and Hashimoto’s thyroiditis were definitively excluded based on serological and imaging profiles.

Genomic DNA was extracted from peripheral blood leukocytes of the proband and his biological parents with written informed consent. Trio whole-exome sequencing identified a heterozygous activating variant in the TSHR gene—a de novo c.1868C>T transition in exon 10. This variant encodes an alanine-to-valine substitution at residue 623 (p.Ala623Val) within transmembrane domain 6, a critical region for G protein coupling. Absent in both parents, this variant was classified as pathogenic under ACMG/AMP guidelines (PS2 + PM1 + PM2 + PP3) (4). Molecular confirmation of this activating TSHR mutation, supported by clinical correlations, definitively established the diagnosis of PSNAH.

The patient was initiated on a combined therapeutic regimen targeting thyrotoxicosis with methimazole (1 mg/kg/day) and metoprolol tartrate (1 mg/kg/day), while continuing preexisting cardiopulmonary support comprising diuretics (furosemide 1 mg/kg/day; spironolactone 0.5 mg/kg/day), strict fluid restriction (≤80 mL/kg/day), and sildenafil (1 mg/kg/day) for PH management. During the initial treatment month, transient symptomatic improvement in heart failure was observed [New York Heart Association (NYHA) class III to II]; however, subsequent respiratory infection triggered acute decompensation accompanied by a marked elevation in NT-proBNP to 14,223 pg/mL. Serial echocardiographic evaluations revealed persistently severe mitral regurgitation with progressive left ventricular dilatation, ultimately requiring surgical intervention. To mitigate the risk of tonsillar herniation during cardiac surgery, staged management was implemented. Firstly, a ventriculoperitoneal shunt was placed two months prior to the procedure, with intraoperative observation of pulsatile cerebrospinal fluid flow confirming elevated intracranial pressure. Eight weeks later, mitral valvuloplasty was performed via median sternotomy under cardiopulmonary bypass, revealing annular dilation and aberrant chordal architecture causing leaflet tethering, without evidence of myxoid degeneration. Postoperatively, complete resolution of heart failure symptoms occurred within 7 days, with 30-day echocardiography demonstrating trace residual mitral regurgitation, left ventricular reverse remodeling, and normalized pulmonary pressures. Longitudinal follow-up confirmed the sustained competence of the affected valves at 5 months. Additionally, thyroid function exhibited a marked improvement 5–9 months following treatment, with TSH levels trending toward the normal reference range. By 18 months post-treatment, thyroid function had achieved full normalization (Table 1).

All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Peking University First Hospital (protocol code 2024463 and date of approval: 25 July 2023). Written informed consent was obtained from the patient’s parents for the publication of this case report and accompanying image. A copy of the written consent is available for review by the editorial office of this journal.

A comprehensive literature review was performed across PubMed, MEDLINE, and EMBASE databases using the keywords “congenital non-autoimmune hyperthyroidism”, identifying 22 molecularly confirmed PSNAH cases (Table 2). Genetic analysis revealed 21 distinct TSHR gain-of-function mutations, with 95.5% (20/21) localized to exon 10-encoded transmembrane domains. The sole extracellular domain mutation (exon 9) demonstrated atypical signaling characteristics in functional studies (9). The cohort demonstrated balanced gender distribution (11 males, 11 females), with 72.7% (16/22) exhibiting fetal or neonatal disease onset (2,5,6,8-10,12-17,19,20,23,25). Skeletal manifestations predominated, including advanced bone age in 63.6% of these patients (14/22) (2,6-8,11-14,16-19,22,24) and craniosynostosis in 31.8% of the cases (7/22) (8-10,14,17,18,24). Neurological involvement affected 36.4% (8/22) of patients, manifesting as developmental delay (2,5,7,8,10,12,14,24), progressive ventriculomegaly (2 cases) (2,14), and one infant requiring ventriculoperitoneal shunting (2). Thyroid abnormalities were observed in 9 cases (2,5-7,13-15,17,18), while cardiovascular complications were rare (2/22, 9.1%) (10,16), limited to arrhythmia and cardiomyopathy without structural valve pathology.

Discussion

This report describes a case of PSNAH presenting with life-threatening multiorgan complications: thyrotoxic mitral valvulopathy requiring surgical repair and ventriculomegaly with tonsillar herniation, adding to the clinical understanding of such manifestations in the condition. Genetic characterization identified a de novo gain-of-function TSHR mutation (c.1868C>T, p.Ala623Val), previously reported in a 6 month-old Turkish boy with PSNAH as well as three cases in one FNAH family, and also as a somatic mutation in a case with toxic nodules (19,26,27).

NAH represents a rare endocrine disorder classifiable into two distinct molecular entities: FNAH and its sporadic counterpart, PSNAH. FNAH demonstrates autosomal dominant inheritance with variable penetrance, whereas PSNAH arises from de novo TSHR mutations correlating with more severe phenotypic expression, as evidenced in our case. Since the seminal 1982 report by Thomas et al. (28), 27 FNAH kindreds and 22 PSNAH cases have been molecularly characterized (2,3,5-25).

The pathophysiological cornerstone of NAH lies in constitutive activation of TSHR signaling. Under physiological conditions, TSH binding induces transient receptor activation through dual G-protein coupling: the Gsα-mediated cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway drives thyrocyte proliferation and follicular growth and the Gq/11-phospholipase Cβ cascade potentiates thyroid hormone synthesis via increased iodide uptake and thyroglobulin proteolysis (29-31). In NAH, germline gain-of-function TSHR mutations cause ligand-independent, persistent activation of these pathways. Notably, cAMP overproduction induces thyroid hyperplasia, while sustained calcium flux from inositol 1,4,5-trisphosphate (IP3)-mediated endoplasmic reticulum (ER) release accelerates T4 biosynthesis, creating the dual hit of gland enlargement and hyperthyroxinemia (3,31,32). This self-perpetuating cycle explains the therapeutic resistance observed in many NAH patients compared to autoimmune Graves’ disease. Paschke et al. identified TSH receptor’s somatic Ala623Val mutation in hyperfunctioning thyroid adenomas and validated it via COS-7 cells: it raised basal cAMP and retained TSH response, matched wild-type in expression and inositol phosphate, showed no cotransfection interaction, confirming pathogenicity for constitutive activation (27).

This case represents the most comprehensive phenotypic manifestation of PSNAH reported to date, encompassing all recognized disease hallmarks: preterm delivery, accelerated skeletal maturation, craniosynostosis, thyromegaly, and Graves-like ophthalmopathy. Crucially, this PSNAH case presents life-threatening thyrotoxic mitral valvulopathy requiring surgical intervention, a feature that distinguishes it from the transient valvular changes typically observed in Graves’ disease and enriches our understanding of the condition’s clinical spectrum. Thyrotoxic valvulopathy, while well-documented in adults with Graves’ disease, remains exceptionally rare in pediatric populations (33-35). The characteristic pathology in Graves’-associated cases involve myxomatous leaflet degeneration with mitral valve prolapse, typically reversible within 6–12 months of euthyroidism restoration (35,36). This phenomenon is mechanistically linked to thyroid hormone-mediated collagen dysregulation through matrix metalloproteinase-9 (MMP-9)/tissue inhibitor of metalloproteinases-1 (TIMP-1) imbalance, causing progressive loss of valvular structural integrity (37-39). Our case presents a distinct pathoanatomic paradigm. Intraoperative evaluation revealed a novel pathoanatomic substrate: redundant chordae tendineae causing leaflet tethering without myxoid degeneration or prolapse. This structural anomaly likely originated from in utero thyroid hormone excess during critical mitral apparatus development. To assess intrauterine hyperthyroidism’s impact on fetal cardiac development, Martinez et al. established a type 3 deiodinase-deficient mouse model. Results showed this condition induced cardiac structural anomalies, perturbed cardiac gene expression, and dysregulated relevant signaling pathways. Though chordae tendineae developmental anomalies were not documented, thyroid hormones’ regulation of gene expression and cardiac conduction pathways implies potential indirect effects (40). Our findings suggest a potential need for early cardiac surveillance in PSNAH. However, given the rarity of genetically confirmed PSNAH cases, our observation of irreversible mitral chordal malformation is insufficient to support generalized cardiac screening guidelines for all PSNAH patients. Instead, it underscores the importance of individualized cardiac assessment in those presenting with clinical signs of cardiac involvement.

The synergistic pathophysiology of severe mitral regurgitation and thyrotoxicosis-induced hyperdynamic circulation precipitated progressive left ventricular remodeling, characterized by chamber dilation and finally congestive heart failure. The rapid resolution of PH following mitral valvuloplasty and heart failure management confirms its secondary nature to left heart disease. This therapeutic response pattern offers a valuable diagnostic consideration: new-onset PH in hyperthyroidism with disproportionate left-sided chamber enlargement warrants urgent valvular assessment.

The presence of hydrocephalus accompanied by cerebellar tonsillar herniation represents a notable neurological manifestation in our PSNAH case. While ventriculomegaly remains an uncommon feature in NAH, documented in only 2 of 23 PSNAH cases (2,14), its co-occurrence with tonsillar herniation in our patient suggests a potential pathophysiological link to craniosynostosis. The premature fusion of cranial sutures likely contributed to elevated intracranial pressure and subsequent ventricular enlargement. This mechanism is further supported by the irreversible nature of ventriculomegaly observed in TSHR mutation carriers despite achieving biochemical euthyroidism, as demonstrated in longitudinal studies (41). Notably, the cerebellar tonsillar herniation observed in our patient resolved 18 months post-treatment, whereas ventriculomegaly remained unchanged. Whether additional neurosurgical intervention will be necessary requires continued longitudinal follow-up.

Therapeutic management of PSNAH remains challenging due to its rarity and absence of randomized controlled trials. Prolonged antithyroid drug therapy effectively controls thyrotoxicosis but carries significant limitations such as thyromegaly and relapse after medication withdrawal (14,18). The European guidelines explicitly emphasize that surgical intervention for PSNAH should be conducted by high-volume thyroid surgeons; meanwhile, early radioiodine therapy is highlighted as a necessary measure to mitigate the risk of disease relapse, with radioiodine treatment recommended for children over 5 years of age (3). In terms of reported clinical cases of PSNAH, among the 22 documented cases, 40.9% (9/22) ultimately required surgical intervention despite initial pharmacological management (5,8-12,18,23,24). Notably, however, there remained one patient who experienced frequent disease relapses even after undergoing surgical treatment (18). Therefore, in the subsequent long-term follow-up of our patient, it will be essential to conduct timely and systematic evaluations to determine the optimal timing for both surgical intervention and radioiodine therapy.

Conclusions

PSNAH is clinically rare but may manifest during the neonatal period or early infancy with features including preterm birth, feeding difficulties, craniosynostosis, and advanced bone age. In this case, the patient exhibited neonatal-onset symptoms; however, delayed diagnosis and treatment led to severe multisystem complications such as valvulopathy, congestive heart failure, ventriculomegaly, and cerebellar tonsillar herniation. These findings underscore the critical importance of neonatal TSHR genetic screening in suspected cases to enable pre-symptomatic management and prevent multiorgan sequelae.

Acknowledgments

The authors extend profound gratitude to the multidisciplinary pediatric care team, cardiothoracic surgeons, and neurodevelopmental specialists involved in this patient’s care. We deeply appreciate the parents’ unwavering trust and informed consent which made this critical documentation of PSNAH’s natural history possible.

Footnote

Reporting Checklist: The authors have completed the CARE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-380/rc

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-380/prf

Funding: None.

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-380/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All procedures performed in this study were in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Ethics Committee of Peking University First Hospital (protocol code 2024463 and date of approval: 25 July 2023). Written informed consent was obtained from the patient’s parents for the publication of this case report and accompanying image. A copy of the written consent is available for review by the editorial office of this journal.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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