RARE DISEASE
Rare hypothyroidism
Rare hypothyroidism
Rare hypothyroidism
Drug discovery
1
drug
With orphan designation
Overview
Rare hypothyroidism encompasses central (secondary) hypothyroidism caused by hypothalamic-pituitary dysfunction, genetic disorders (e.g., thyroid hormone resistance, congenital defects), and infiltrative diseases [1][12][18]. Diagnosis requires measuring free T4 and TSH, as standard TSH-guided dosing does not apply [1][10]. Treatment focuses on levothyroxine titration, with careful monitoring to avoid complications like adrenal crisis in pituitary dysfunction [1][9].
Categories: rare endocrine diseases, rare genetic diseases
Research Papers
421 drug discovery papers about Rare hypothyroidism. Recent publications:
421 drug discovery papers about Rare hypothyroidism. Recent publications:
categories:
Small molecules
small molecules
2026-09-29 | Frail, Fluid, and Falsely Accused: Myxedema Ascites in an Older Adult.
Ascites is a rare presentation of hypothyroidism and can be easily mistaken for malignancy when it occurs alongside pleural effusion and radiological lymphadenopathy. We report the case of a 63-year-old man who presented with progressive generalized anasarca, abdominal distension, and worsening breathlessness. Diagnostic paracentesis revealed exudative ascites with a low serum-ascites albumin gradient (SAAG) and markedly elevated protein content, and thyroid function testing showed profound, previously undiagnosed primary hypothyroidism (thyroid-stimulating hormone (TSH) 221.2 µIU/mL). On a subsequent admission, contrast-enhanced CT additionally revealed bilateral pleural effusion with mediastinal lymphadenopathy and omental fat stranding, raising concern for an underlying malignant or granulomatous process. Repeat ascitic fluid analysis, cytology, tumor markers, and cartridge-based nucleic acid amplification test (CBNAAT) were unremarkable, and an omental biopsy was performed and was not suggestive of inflammatory pathology; in view of this reassuring result, together with the patient's frailty and early clinical improvement, the higher-risk procedure, mediastinal lymph node biopsy, was deferred by multidisciplinary consensus in favor of a trial of thyroid hormone replacement. This strategy proved correct: with initiation and titration of levothyroxine, the patient's ascites, pleural effusion, and edema resolved completely on serial follow-up, obviating the need for mediastinal lymph node sampling. This case illustrates that myxedema ascites can radiologically mimic malignancy and that thyroid function testing, together with judicious, risk-stratified tissue sampling and, where clinically appropriate, a closely monitored trial of thyroid hormone replacement, can help a frail older adult avoid an unnecessary high-risk biopsy.
2026-07-17 | A novel homozygous thyroglobulin gene variant presenting with massive congenital goiter and neonatal airway obstruction.
Congenital hypothyroidism due to thyroid dyshormonogenesis is a rare inherited disorder that may present with goiter of variable severity. Massive congenital goiter causing life-threatening respiratory distress at birth is exceptionally uncommon. We report a late-preterm male neonate who presented immediately after delivery with severe respiratory failure requiring endotracheal intubation due to critical tracheal compression caused by a massive congenital goiter. Postnatal imaging revealed marked thyroid hyperplasia with airway narrowing. Thyroid function tests demonstrated isolated low free thyroxine (fT4) levels with normal thyroid-stimulating hormone (TSH), a pattern attributed to non-thyroidal illness syndrome related to perinatal asphyxia and inotropic support. Therapeutic-dose levothyroxine was initiated, resulting in a progressive reduction in goiter size and successful extubation. Genetic analysis using next-generation sequencing identified a previously unreported homozygous missense variant in the thyroglobulin gene, supporting the diagnosis of thyroglobulin-related dyshormonogenetic congenital hypothyroidism. This case highlights that congenital goiter should be considered in neonates presenting with respiratory distress at birth, even in the absence of elevated TSH levels or prenatal findings. It underscores the importance of early diagnosis, genetic evaluation, and timely levothyroxine therapy to prevent airway compromise and ensure favorable outcomes.
2026-07-09 | Clinical outcomes of thyroid function in patients with thyrotropin receptor blocking antibody-positive hypothyroidism.
Thyrotropin receptor blocking antibodies (TBAbs) are uncommon but not a rare cause of hypothyroidism. However, clinical outcomes of thyroid function in patients with TBAb-positive hypothyroidism remain unclear. The aim of this study was to explore the clinical outcomes of thyroid function in patients with TBAb-positive hypothyroidism and investigate factors associated with hypothyroidism outcomes. A single-center retrospective observational study was conducted from 2024 to 2025. Overall, 137 patients with TBAb-positive hypothyroidism without Graves' disease (Non-GD group) and 181 with TBAb-positive hypothyroidism during or after antithyroid drug therapy for Graves' disease (Prior GD group), almost all Japanese, were included. Thyroid functional outcomes were assessed in all patients; serial TBAb measurements were available for 31% and 36% of the patients, respectively. The main outcome was thyroid function at the final visit after a median follow-up period of 6.8 years. Clinical factors associated with hypothyroidism outcomes were analyzed using logistic regression analysis. Hypothyroidism persisted in 84% and 43% of the patients in the Non-GD and Prior GD groups, respectively. In both groups, persistent TBAb positivity was associated with hypothyroid outcomes (Non-GD: univariate analysis, odds ratio [OR], 3.51; 95% CI, 1.14-40.6; P = .013; Prior GD: univariate analysis, OR, 6.75; 95% CI, 1.87-24.4; P = .0016; multivariate analysis, OR, 6.88; 95% CI, 1.89-25.1; P = .0015). Most patients with TBAb-positive hypothyroidism remain hypothyroid over the long term, whereas outcomes are more heterogeneous in patients with prior Graves' disease who develop TBAb-positive hypothyroidism. Persistent TBAb positivity is associated with the hypothyroidism outcomes.
2026-07-02 | Headache as the Primary Manifestation of Pituitary Hyperplasia Secondary to Primary Hypothyroidism: A Case Report.
Pituitary hyperplasia secondary to primary hypothyroidism (PHPH) is a rare condition caused by untreated hypothyroidism, leading to thyrotroph proliferation and pituitary enlargement. Common manifestations include growth disorders, obesity, and hormonal imbalances. PHPH may also present with headaches due to pituitary mass effects, though this is less frequently reported. Despite iodine fortification programs, subclinical hypothyroidism remains prevalent in certain regions. PHPH is often misdiagnosed as pituitary adenoma, emphasizing the need for clinical awareness, particularly in adolescents with atypical symptoms like headaches without classic hypothyroid features. A 16-year-old female presented with severe, medication-resistant headaches, photophobia, and nausea. MRI revealed pituitary enlargement (12 × 11 × 9 mm) and a Rathke's cleft cyst. Laboratory tests confirmed severe primary hypothyroidism (thyroid-stimulating hormone [TSH]: 117 mIU/L [reference range 0.4-4.5], free T4: 0.34 ng/dL [RR: 0.8-1.8]) and thyroid atrophy on ultrasound. Levothyroxine therapy normalized TSH (2.6 mIU/L) and free T4 (1.26 ng/dL) within 3 months, resolving galactorrhea and improving headaches. Discontinuing treatment led to headache recurrence and elevated thyroid peroxidase antibodies (488 IU/mL), confirming autoimmune thyroiditis as the underlying cause. Reinitiating levothyroxine resolved symptoms, underscoring PHPH's role in her presentation. This case highlights PHPH as a rare cause of secondary headaches in adolescents, even without classic hypothyroid symptoms like menstrual irregularities. Timely diagnosis via MRI and thyroid function testing is critical to avoid mismanagement. Levothyroxine effectively reverses pituitary hyperplasia and alleviates symptoms, but long-term adherence is essential to prevent relapse. Clinicians should consider endocrine etiologies in unexplained headaches, particularly in cases resistant to conventional therapies, to ensure prompt intervention and improved outcomes.
2026-06-25 | Visual Hallucinations and Cognitive Impairment as the Initial Presentation of Severe Hypothyroidism in an Elderly Patient: A Case Report.
Background: Hypothyroidism is a prevalent endocrine disorder capable of affecting multiple organ systems. While somatic symptoms are common, prominent neuropsychiatric manifestations such as visual hallucinations and cognitive deficits are exceptionally rare as an initial presentation. This atypical clinical picture frequently leads to misdiagnosis as primary psychiatric disorders or neurodegenerative conditions. Case Presentation: We report the case of a 75-year-old male who presented with a three-month history of complex visual hallucinations and progressive cognitive decline. The hallucinations were notably dependent on environmental light. Initial assessments raised concerns about the neurodegenerative process. However, laboratory investigations revealed severe autoimmune hypothyroidism with high titers of anti-thyroid antibodies. Following timely levothyroxine replacement therapy, the patient achieved complete remission of visual hallucinations and significant cognitive recovery. Conclusions: This case illustrates that severe hypothyroidism can manifest as a reversible metabolic encephalopathy mimicking dementia. It underscores the importance of screening for thyroid dysfunction in elderly patients presenting with unexplained acute neuropsychiatric symptoms to ensure appropriate management.
proteins
2026-09-08 | [Fulminant blood sugar increase - a rare but life-threatening course].
A 71-year-old patient with known metastatic melanoma undergoing treatment with the immune checkpoint inhibitors Ipilimumab/Nivolumab presented with a rapid deterioration in general condition over the past 24 hours. Approximately three weeks after starting ICI-the-rapy, thyroiditis was diagnosed, which progressed to a substitution-requiring hypothyroidism. Currently, laboratory tests revealed severe keto-acidosis with acute blood sugar derangement (51 mmol/l) despite only a mildly elevated HbA1c (6.3 %). We hereby diagnosed fulminant ICI- associated type 1 diabetes mellitus. Symptoms improved under insulin therapy.
2025-06-26 | Pituitary Apoplexy in a Child with Short Stature and Possible Recent SARS-CoV-2 Infection.
Background and Clinical Significance: Pituitary apoplexy is an extremely rare condition in children and adolescents with a rapid onset due to acute hemorrhage, infarction, or both in the pituitary gland. Most frequently, pituitary apoplexy is an asymptomatic or subclinical entity. Few cases of pituitary apoplexy with concurrent SARS-CoV-2 infection or COVID-19 vaccination have been reported. Case Presentation: We present the case of a 13-year-8-month-old boy who presented in our pediatric endocrinology department for the evaluation of short stature. He was previously diagnosed with secondary hypothyroidism and was treated with levothyroxine. At admission, clinical examination revealed a height of 141 cm (-2.68 SD/-2.4 SD corrected for mid-parental height), normal weight (60th centile), Tanner-stage G2P1, and delayed bone age. Basal IGF1 was normal, but the tests performed to assess the GH reserve confirmed the GH deficiency (peak GH value 3.11 ng/mL after clonidine/0.95 ng/mL after insulin). The brain MRI revealed a subacute pituitary hemorrhage. Thrombophilia and coagulopathies were excluded by further testing. Anti-SARS-CoV-2 (anti-S-protein IgG) antibodies (>200 BAU/mL) were compatible with COVID-19 infection, indicating a possible association between these two entities. At 3-month follow-up, physical examination showed a 3 cm height gain and advancing pubertal development (G4P2). Newer MRI found changes consistent with resolving hemorrhage. The patient was provided immediately with recombinant human GH and aromatase inhibitor therapy to maximize GH treatment response. During follow-up, the rGH dose was adjusted based on IGF1 values, and after 3 years and 10 months, rGH treatment was stopped, reaching a height of 172.3 cm (-0.51 SD) and surpassing the initial prediction of 164.5 cm. Conclusions: Pituitary apoplexy, an even rarer complication in the pediatric population, may be associated with SARS-CoV-2 infection. Further studies are necessary to better understand the intertwining of those conditions.
2024-07-19 | Rare Case of Growth Hormone Insensitivity Syndrome Correlated With Hypothyroidism: A Case Report.
Growth hormone insensitivity syndrome (GHIS) is a rare genetic disorder characterized by short stature due to the body's inability to effectively utilize growth hormone (GH). This case report describes a patient with concurrent hypothyroidism and GHIS. This patient is an 11-year-old female presented with short stature; general examination suggested a prominent forehead and a depressed nasal bridge. Laboratory evaluations revealed elevated thyroid-stimulating hormone (TSH) levels alongside low levels of triiodothyronine (T3) and thyroxine (T4), indicating hypothyroidism. Additionally, elevated GH levels and significantly reduced insulin-like growth factor 1 (IGF-1) levels confirmed the diagnosis of GHIS. The patient was managed with thyroid hormone replacement therapy and recombinant GH. This dual therapeutic approach will lead to improvements in both thyroid function and growth parameters. This case underscores the importance of recognizing and addressing coexisting endocrine disorders in patients with GHIS to optimize their growth and developmental outcomes. Early diagnosis and a comprehensive treatment strategy are essential for managing such complex cases effectively.
2024-05-15 | Clinical Characteristics of Children with THRA Mutations: Variable Phenotype and Good Response to Recombinant Human Growth Hormone Therapy.
Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range. THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.
2021-09-02 | Phenotypic Variability of Patients With PAX8 Variants Presenting With Congenital Hypothyroidism and Eutopic Thyroid.
Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.
antibodies
2026-03-16 | PLA2R-positive primary membranous nephropathy in an adolescent with type 1 diabetes mellitus and autoimmune hypothyroidism: a case report.
Membranous nephropathy (MN) is an uncommon cause of nephrotic syndrome in children, accounting for fewer than 5% of cases. Primary MN mediated by antibodies against the phospholipase A2 receptor (PLA2R) is particularly rare in the paediatric population. We report the case of a 14-year-old girl with type 1 diabetes mellitus and autoimmune hypothyroidism who presented with nephrotic syndrome and was subsequently diagnosed with PLA2R-positive primary MN. She presented with periorbital oedema, abdominal distension, and bilateral pitting pedal oedema. Laboratory investigations demonstrated severe hypoalbuminemia (serum albumin 1.2 g/dL), nephrotic-range proteinuria (24-hour urine protein excretion of 3.5 g/day), and preserved renal function (serum creatinine 0.3 mg/dL). Renal biopsy findings, supported by immunohistochemistry, confirmed PLA2R positivity. The patient was treated with four weekly doses of rituximab (375 mg/m2), resulting in complete clinical remission at 6 months. Serum albumin normalised to 4 g/dL, 24-hour urine protein excretion decreased to 250 mg/day, and serum PLA2R antibody levels fell below the normal range. This case highlights the importance of considering PLA2R-mediated MN in adolescents with nephrotic syndrome and the presence of multiple autoimmune comorbidities. It also underscores the diagnostic value of tissue PLA2R testing and demonstrates the efficacy of early rituximab-based B-cell-directed therapy in achieving complete remission while avoiding corticosteroid exposure.
2025-10-30 | [Mixed type II cryoglobulinemiaassociated glomerulonephritis revealing an extragastric marginal zone lymphoma in the absence of viral infection: A rare case report from Bourges Hospital].
Type II mixed cryoglobulinemia is most commonly associated with chronic hepatitis C virus infection. The occurrence of marginal zone lymphoma as the underlying cause is rare, especially in the absence of gastric involvement. A 63-year-old woman with hypertension and hypothyroidism initially presented with transient purpura following a urinary tract infection. Two months later, she developed acute kidney injury, proteinuria (2.3 g/24 h), and microscopic hematuria. Laboratory tests showed type II mixed cryoglobulinemia (IgM κ + IgG) with hypocomplementemia. Viral serologies, including HCV, were negative. Renal biopsy revealed membranoproliferative glomerulonephritis with IgM and IgG deposits. Blood and bone marrow immunophenotyping confirmed an extragastric marginal zone lymphoma. The patient was treated with six cycles of rituximab-bendamustine. Complete remission was achieved: recovery of renal function (creatinine 84 μmol/L at 12 months), resolution of proteinuria, improvement of anemia, and regression of splenomegaly. No relapse was observed after 18 months of follow-up. This case represents a particularly rare presentation of type II mixed cryoglobulinemia revealing an extragastric marginal zone lymphoma in the absence of viral infection or gastric involvement. It contributes to the sparse literature on this uncommon association. Treatment with rituximab-bendamustine appears to be effective.
2024-09-12 | Defective thyroid hormone transport to the brain leads to astroglial alterations.
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
2024-07-15 | Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.
The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.
2024-02-07 | Superior Orbital Fissure Syndrome in the Setting of Relapsing Polychondritis with Concurrent Sjogren's Syndrome: A Case Report.
Ophthalmic manifestations of varying severity are often associated with systemic autoimmune conditions. Superior orbital fissure syndrome (SOFS) is a rare cranial neuropathy affecting nerves passing through the superior orbital fissure that causes a distinctive pattern of extraocular and pupillary findings. We report the coexistence of SOFS, relapsing polychondritis (RP) and Sjögren's syndrome (SS) in a 52-year-old female who presented with a past medical history of hypothyroidism, Raynaud's syndrome, and intermittent dry mouth and a 1-week history of worsening chemosis, proptosis, diplopia, and painful ophthalmoplegia. Following a comprehensive eye examination, the patient underwent a CT head with contrast, MRI of the orbit, lumbar puncture, and laboratory investigations. CT and MRI examination revealed inflammatory standing in periorbital subcutaneous soft tissues and bilateral exophthalmos with right intraconal fat stranding surrounding the intraorbital and intracanalicular segments of the nerve, respectively. Lumbar puncture and laboratory investigations revealed an elevation in inflammatory biomarkers, a negative infectious workup, and ruled in SS when considering her history alongside a positive Schirmer test. She was started on high-dose steroids, which led to significant improvement; however, treatment revealed type 2 diabetes, necessitating a faster steroid taper, during which there was a reoccurrence of scleritis and ophthalmoplegia, leading to the initiation of rituximab infusions. After completing rituximab course, she was transitioned back to steroid therapy and was successfully tapered without event. This case is notable for the rare coexistence of SOFS with RP/SS overlap syndrome and highlights the management of concurrent orbital inflammatory syndrome and autoimmune diseases.
oligonucleotides
2025-05-05 | LncRNA Dio3os regulates neighboring gene Dio3 and impacts osteogenesis in trans.
Consumptive hypothyroidism, a rare pediatric disorder, arises from aberrant Dio3 expression, which inactivates thyroid hormones and disrupts skeletal development. This study investigates the regulatory role of the long non-coding RNA Dio3os, which activates Dio3 in cis and suppresses osteoblast differentiation in trans. We focused on mouse Dio3os variant 203 and human variants 203 and 205. Chromatin accessibility and histone modification analyses revealed higher chromatin openness and active histone H3 modifications at the Dio3os promoter and exons 2 and 3, followed by increased RUNX2 binding with reduced histone H3 modifications during maturation. Dio3os expression is enhanced by HDAC1/2, HIF1a, and thyroid hormones, but repressed by BMP2, TGFb, Runx2, and Brg1. Overexpression of Dio3os upregulated Dio3 while downregulating osteogenic markers. CRISPR-mediated deletion of Dio3os exons or premature intronic polyadenylation suppressed Dio3 and restored osteogenic gene expression. RNA-seq and ATAC-seq confirmed enhanced thyroid hormone-responsive osteoblast gene activity in Dio3os-CRISPR-knockout cells. These findings reveal Dio3os as a key regulator of thyroid hormone metabolism and bone formation, presenting a novel target for treating skeletal abnormalities in early childhood hypothyroidism.
2021-10-20 | ZFP36L2 Role in Thyroid Functionality.
Thyroid hormone levels are usually genetically determined. Thyrocytes produce a unique set of enzymes that are dedicated to thyroid hormone synthesis. While thyroid transcriptional regulation is well-characterized, post-transcriptional mechanisms have been less investigated. Here, we describe the involvement of ZFP36L2, a protein that stimulates degradation of target mRNAs, in thyroid development and function, by in vivo and in vitro gene targeting in thyrocytes. Thyroid-specific Zfp36l2-/- females were hypothyroid, with reduced levels of circulating free Thyroxine (cfT4) and Triiodothyronine (cfT3). Their hypothyroidism was due to dyshormonogenesis, already evident one week after weaning, while thyroid development appeared normal. We observed decreases in several thyroid-specific transcripts and proteins, such as Nis and its transcriptional regulators (Pax8 and Nkx2.1), and increased apoptosis in Zfp36l2-/- thyroids. Nis, Pax8, and Nkx2.1 mRNAs were also reduced in Zfp36l2 knock-out thyrocytes in vitro (L2KO), in which we confirmed the increased apoptosis. Finally, in L2KO cells, we showed an altered response to TSH stimulation regarding both thyroid-specific gene expression and cell proliferation and survival. This result was supported by increases in P21/WAF1 and p-P38MAPK levels. Mechanistically, we confirmed Notch1 as a target of ZFP36L2 in the thyroid since its levels were increased in both in vitro and in vivo models. In both models, the levels of Id4 mRNA, a potential inhibitor of Pax8 activity, were increased. Overall, the data indicate that the regulation of mRNA stability by ZFP36L2 is a mechanism that controls the function and survival of thyrocytes.
2016-08-12 | JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects.
The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.
other
2022-11-01 | A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations.
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.
2022-08-30 | Whole-exome analysis of 177 pediatric patients with undiagnosed diseases.
Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24-35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.
2017-10-04 | Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq.
Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (TRH) receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood. Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms. All family members were phenotyped with thyroid hormone profiles, pituitary magnetic resonance imaging, TRH tests, and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB, and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling. A homozygous missense mutation in TRHR (c.392T > C; p.I131T) was identified in an 8-year-old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; -0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq. A unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.
small molecules
2026-09-29 | Frail, Fluid, and Falsely Accused: Myxedema Ascites in an Older Adult.
Ascites is a rare presentation of hypothyroidism and can be easily mistaken for malignancy when it occurs alongside pleural effusion and radiological lymphadenopathy. We report the case of a 63-year-old man who presented with progressive generalized anasarca, abdominal distension, and worsening breathlessness. Diagnostic paracentesis revealed exudative ascites with a low serum-ascites albumin gradient (SAAG) and markedly elevated protein content, and thyroid function testing showed profound, previously undiagnosed primary hypothyroidism (thyroid-stimulating hormone (TSH) 221.2 µIU/mL). On a subsequent admission, contrast-enhanced CT additionally revealed bilateral pleural effusion with mediastinal lymphadenopathy and omental fat stranding, raising concern for an underlying malignant or granulomatous process. Repeat ascitic fluid analysis, cytology, tumor markers, and cartridge-based nucleic acid amplification test (CBNAAT) were unremarkable, and an omental biopsy was performed and was not suggestive of inflammatory pathology; in view of this reassuring result, together with the patient's frailty and early clinical improvement, the higher-risk procedure, mediastinal lymph node biopsy, was deferred by multidisciplinary consensus in favor of a trial of thyroid hormone replacement. This strategy proved correct: with initiation and titration of levothyroxine, the patient's ascites, pleural effusion, and edema resolved completely on serial follow-up, obviating the need for mediastinal lymph node sampling. This case illustrates that myxedema ascites can radiologically mimic malignancy and that thyroid function testing, together with judicious, risk-stratified tissue sampling and, where clinically appropriate, a closely monitored trial of thyroid hormone replacement, can help a frail older adult avoid an unnecessary high-risk biopsy.
2026-07-17 | A novel homozygous thyroglobulin gene variant presenting with massive congenital goiter and neonatal airway obstruction.
Congenital hypothyroidism due to thyroid dyshormonogenesis is a rare inherited disorder that may present with goiter of variable severity. Massive congenital goiter causing life-threatening respiratory distress at birth is exceptionally uncommon. We report a late-preterm male neonate who presented immediately after delivery with severe respiratory failure requiring endotracheal intubation due to critical tracheal compression caused by a massive congenital goiter. Postnatal imaging revealed marked thyroid hyperplasia with airway narrowing. Thyroid function tests demonstrated isolated low free thyroxine (fT4) levels with normal thyroid-stimulating hormone (TSH), a pattern attributed to non-thyroidal illness syndrome related to perinatal asphyxia and inotropic support. Therapeutic-dose levothyroxine was initiated, resulting in a progressive reduction in goiter size and successful extubation. Genetic analysis using next-generation sequencing identified a previously unreported homozygous missense variant in the thyroglobulin gene, supporting the diagnosis of thyroglobulin-related dyshormonogenetic congenital hypothyroidism. This case highlights that congenital goiter should be considered in neonates presenting with respiratory distress at birth, even in the absence of elevated TSH levels or prenatal findings. It underscores the importance of early diagnosis, genetic evaluation, and timely levothyroxine therapy to prevent airway compromise and ensure favorable outcomes.
2026-07-09 | Clinical outcomes of thyroid function in patients with thyrotropin receptor blocking antibody-positive hypothyroidism.
Thyrotropin receptor blocking antibodies (TBAbs) are uncommon but not a rare cause of hypothyroidism. However, clinical outcomes of thyroid function in patients with TBAb-positive hypothyroidism remain unclear. The aim of this study was to explore the clinical outcomes of thyroid function in patients with TBAb-positive hypothyroidism and investigate factors associated with hypothyroidism outcomes. A single-center retrospective observational study was conducted from 2024 to 2025. Overall, 137 patients with TBAb-positive hypothyroidism without Graves' disease (Non-GD group) and 181 with TBAb-positive hypothyroidism during or after antithyroid drug therapy for Graves' disease (Prior GD group), almost all Japanese, were included. Thyroid functional outcomes were assessed in all patients; serial TBAb measurements were available for 31% and 36% of the patients, respectively. The main outcome was thyroid function at the final visit after a median follow-up period of 6.8 years. Clinical factors associated with hypothyroidism outcomes were analyzed using logistic regression analysis. Hypothyroidism persisted in 84% and 43% of the patients in the Non-GD and Prior GD groups, respectively. In both groups, persistent TBAb positivity was associated with hypothyroid outcomes (Non-GD: univariate analysis, odds ratio [OR], 3.51; 95% CI, 1.14-40.6; P = .013; Prior GD: univariate analysis, OR, 6.75; 95% CI, 1.87-24.4; P = .0016; multivariate analysis, OR, 6.88; 95% CI, 1.89-25.1; P = .0015). Most patients with TBAb-positive hypothyroidism remain hypothyroid over the long term, whereas outcomes are more heterogeneous in patients with prior Graves' disease who develop TBAb-positive hypothyroidism. Persistent TBAb positivity is associated with the hypothyroidism outcomes.
2026-07-02 | Headache as the Primary Manifestation of Pituitary Hyperplasia Secondary to Primary Hypothyroidism: A Case Report.
Pituitary hyperplasia secondary to primary hypothyroidism (PHPH) is a rare condition caused by untreated hypothyroidism, leading to thyrotroph proliferation and pituitary enlargement. Common manifestations include growth disorders, obesity, and hormonal imbalances. PHPH may also present with headaches due to pituitary mass effects, though this is less frequently reported. Despite iodine fortification programs, subclinical hypothyroidism remains prevalent in certain regions. PHPH is often misdiagnosed as pituitary adenoma, emphasizing the need for clinical awareness, particularly in adolescents with atypical symptoms like headaches without classic hypothyroid features. A 16-year-old female presented with severe, medication-resistant headaches, photophobia, and nausea. MRI revealed pituitary enlargement (12 × 11 × 9 mm) and a Rathke's cleft cyst. Laboratory tests confirmed severe primary hypothyroidism (thyroid-stimulating hormone [TSH]: 117 mIU/L [reference range 0.4-4.5], free T4: 0.34 ng/dL [RR: 0.8-1.8]) and thyroid atrophy on ultrasound. Levothyroxine therapy normalized TSH (2.6 mIU/L) and free T4 (1.26 ng/dL) within 3 months, resolving galactorrhea and improving headaches. Discontinuing treatment led to headache recurrence and elevated thyroid peroxidase antibodies (488 IU/mL), confirming autoimmune thyroiditis as the underlying cause. Reinitiating levothyroxine resolved symptoms, underscoring PHPH's role in her presentation. This case highlights PHPH as a rare cause of secondary headaches in adolescents, even without classic hypothyroid symptoms like menstrual irregularities. Timely diagnosis via MRI and thyroid function testing is critical to avoid mismanagement. Levothyroxine effectively reverses pituitary hyperplasia and alleviates symptoms, but long-term adherence is essential to prevent relapse. Clinicians should consider endocrine etiologies in unexplained headaches, particularly in cases resistant to conventional therapies, to ensure prompt intervention and improved outcomes.
2026-06-25 | Visual Hallucinations and Cognitive Impairment as the Initial Presentation of Severe Hypothyroidism in an Elderly Patient: A Case Report.
Background: Hypothyroidism is a prevalent endocrine disorder capable of affecting multiple organ systems. While somatic symptoms are common, prominent neuropsychiatric manifestations such as visual hallucinations and cognitive deficits are exceptionally rare as an initial presentation. This atypical clinical picture frequently leads to misdiagnosis as primary psychiatric disorders or neurodegenerative conditions. Case Presentation: We report the case of a 75-year-old male who presented with a three-month history of complex visual hallucinations and progressive cognitive decline. The hallucinations were notably dependent on environmental light. Initial assessments raised concerns about the neurodegenerative process. However, laboratory investigations revealed severe autoimmune hypothyroidism with high titers of anti-thyroid antibodies. Following timely levothyroxine replacement therapy, the patient achieved complete remission of visual hallucinations and significant cognitive recovery. Conclusions: This case illustrates that severe hypothyroidism can manifest as a reversible metabolic encephalopathy mimicking dementia. It underscores the importance of screening for thyroid dysfunction in elderly patients presenting with unexplained acute neuropsychiatric symptoms to ensure appropriate management.
proteins
2026-09-08 | [Fulminant blood sugar increase - a rare but life-threatening course].
A 71-year-old patient with known metastatic melanoma undergoing treatment with the immune checkpoint inhibitors Ipilimumab/Nivolumab presented with a rapid deterioration in general condition over the past 24 hours. Approximately three weeks after starting ICI-the-rapy, thyroiditis was diagnosed, which progressed to a substitution-requiring hypothyroidism. Currently, laboratory tests revealed severe keto-acidosis with acute blood sugar derangement (51 mmol/l) despite only a mildly elevated HbA1c (6.3 %). We hereby diagnosed fulminant ICI- associated type 1 diabetes mellitus. Symptoms improved under insulin therapy.
2025-06-26 | Pituitary Apoplexy in a Child with Short Stature and Possible Recent SARS-CoV-2 Infection.
Background and Clinical Significance: Pituitary apoplexy is an extremely rare condition in children and adolescents with a rapid onset due to acute hemorrhage, infarction, or both in the pituitary gland. Most frequently, pituitary apoplexy is an asymptomatic or subclinical entity. Few cases of pituitary apoplexy with concurrent SARS-CoV-2 infection or COVID-19 vaccination have been reported. Case Presentation: We present the case of a 13-year-8-month-old boy who presented in our pediatric endocrinology department for the evaluation of short stature. He was previously diagnosed with secondary hypothyroidism and was treated with levothyroxine. At admission, clinical examination revealed a height of 141 cm (-2.68 SD/-2.4 SD corrected for mid-parental height), normal weight (60th centile), Tanner-stage G2P1, and delayed bone age. Basal IGF1 was normal, but the tests performed to assess the GH reserve confirmed the GH deficiency (peak GH value 3.11 ng/mL after clonidine/0.95 ng/mL after insulin). The brain MRI revealed a subacute pituitary hemorrhage. Thrombophilia and coagulopathies were excluded by further testing. Anti-SARS-CoV-2 (anti-S-protein IgG) antibodies (>200 BAU/mL) were compatible with COVID-19 infection, indicating a possible association between these two entities. At 3-month follow-up, physical examination showed a 3 cm height gain and advancing pubertal development (G4P2). Newer MRI found changes consistent with resolving hemorrhage. The patient was provided immediately with recombinant human GH and aromatase inhibitor therapy to maximize GH treatment response. During follow-up, the rGH dose was adjusted based on IGF1 values, and after 3 years and 10 months, rGH treatment was stopped, reaching a height of 172.3 cm (-0.51 SD) and surpassing the initial prediction of 164.5 cm. Conclusions: Pituitary apoplexy, an even rarer complication in the pediatric population, may be associated with SARS-CoV-2 infection. Further studies are necessary to better understand the intertwining of those conditions.
2024-07-19 | Rare Case of Growth Hormone Insensitivity Syndrome Correlated With Hypothyroidism: A Case Report.
Growth hormone insensitivity syndrome (GHIS) is a rare genetic disorder characterized by short stature due to the body's inability to effectively utilize growth hormone (GH). This case report describes a patient with concurrent hypothyroidism and GHIS. This patient is an 11-year-old female presented with short stature; general examination suggested a prominent forehead and a depressed nasal bridge. Laboratory evaluations revealed elevated thyroid-stimulating hormone (TSH) levels alongside low levels of triiodothyronine (T3) and thyroxine (T4), indicating hypothyroidism. Additionally, elevated GH levels and significantly reduced insulin-like growth factor 1 (IGF-1) levels confirmed the diagnosis of GHIS. The patient was managed with thyroid hormone replacement therapy and recombinant GH. This dual therapeutic approach will lead to improvements in both thyroid function and growth parameters. This case underscores the importance of recognizing and addressing coexisting endocrine disorders in patients with GHIS to optimize their growth and developmental outcomes. Early diagnosis and a comprehensive treatment strategy are essential for managing such complex cases effectively.
2024-05-15 | Clinical Characteristics of Children with THRA Mutations: Variable Phenotype and Good Response to Recombinant Human Growth Hormone Therapy.
Mutations in the thyroid hormone receptor alpha (THRA) gene are a rare cause of thyroid hormone resistance, which leads to a pleomorphic phenotypic spectrum. Hormonal profiles are variable and subtle, making laboratory diagnoses challenging. Genetic evaluation can be a helpful tool in diagnosing these cases. Three patients (P1, P2, and P3) from unrelated families presented to their endocrinologists with short stature and abnormalities in thyroid function results. P1 showed hypoactivity and mild thyroid-stimulating hormone (TSH) elevation. P2 presented with a mild developmental delay and a hormonal profile initially interpreted as central hypothyroidism. Patient P3 had severe symptoms, including hypotonia, developmental delay, normal TSH, hypercholesterolemia, severe hypertriglyceridemia, high amylase levels, and mild pericardial effusion. All the patients had low free thyroxine (FT4) levels, mild constipation, and short stature. The patients underwent exome sequencing analysis that identified three different heterozygous variants in the THRA gene (P1 and P2 had missense variants, and P3 had a stop codon variant). All patients were treated with levothyroxine replacement, improving their clinical symptoms, such as constipation, and neurological symptoms. P1 and P2 were also treated with the recombinant human growth hormone (rhGH). The improvements in growth velocity and height standard deviation scores (SDS) were remarkable. Notably, P1 had a total height gain of 2.5 SDS, reaching an adult height within the normal range. THRA gene defects can lead to growth disorders with different phenotypes. Children with THRA mutations can benefit from adequate treatment with levothyroxine and may respond well to rhGH treatment.
2021-09-02 | Phenotypic Variability of Patients With PAX8 Variants Presenting With Congenital Hypothyroidism and Eutopic Thyroid.
Thyroid dyshormonogenesis is a heterogeneous group of hereditary diseases produced by a total/partial blockage of the biochemical processes of thyroid-hormone synthesis and secretion. Paired box 8 (PAX8) is essential for thyroid morphogenesis and thyroid hormone synthesis. We aimed to identify PAX8 variants in patients with thyroid dyshormonogenesis and to analyze them with in vitro functional studies. Nine pediatric patients with a eutopic thyroid gland were analyzed by the Catalan screening program for congenital hypothyroidism. Scintigraphies showed absent, low, or normal uptake. Only one patient had a hypoplastic gland. On reevaluation, perchlorate discharge test was negative or compatible with partial iodine-organization deficit. After evaluation, 8 patients showed permanent mild or severe hypothyroidism. Massive-sequencing techniques were used to detect variants in congenital hypothyroidism-related genes. In vitro functional studies were based on transactivating activity of mutant PAX8 on a TG-gene promoter and analyzed by a dual-luciferase assays. We identified 7 heterozygous PAX8 exonic variants and 1 homozygous PAX8 splicing variant in 9 patients with variable phenotypes of thyroid dyshormonogenesis. Five were novel and 5 variants showed a statistically significant impaired transcriptional activity of TG promoter: 51% to 78% vs the wild type. Nine patients presented with PAX8 candidate variants. All presented with a eutopic thyroid gland and 7 had deleterious variants. The phenotype of affected patients varies considerably, even within the same family; but, all except the homozygous patient presented with a normal eutopic thyroid gland and thyroid dyshormonogenesis. PAX8 functional studies have shown that 6 PAX8 variants are deleterious. Our studies have proven effective in evaluating these variants.
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2026-03-16 | PLA2R-positive primary membranous nephropathy in an adolescent with type 1 diabetes mellitus and autoimmune hypothyroidism: a case report.
Membranous nephropathy (MN) is an uncommon cause of nephrotic syndrome in children, accounting for fewer than 5% of cases. Primary MN mediated by antibodies against the phospholipase A2 receptor (PLA2R) is particularly rare in the paediatric population. We report the case of a 14-year-old girl with type 1 diabetes mellitus and autoimmune hypothyroidism who presented with nephrotic syndrome and was subsequently diagnosed with PLA2R-positive primary MN. She presented with periorbital oedema, abdominal distension, and bilateral pitting pedal oedema. Laboratory investigations demonstrated severe hypoalbuminemia (serum albumin 1.2 g/dL), nephrotic-range proteinuria (24-hour urine protein excretion of 3.5 g/day), and preserved renal function (serum creatinine 0.3 mg/dL). Renal biopsy findings, supported by immunohistochemistry, confirmed PLA2R positivity. The patient was treated with four weekly doses of rituximab (375 mg/m2), resulting in complete clinical remission at 6 months. Serum albumin normalised to 4 g/dL, 24-hour urine protein excretion decreased to 250 mg/day, and serum PLA2R antibody levels fell below the normal range. This case highlights the importance of considering PLA2R-mediated MN in adolescents with nephrotic syndrome and the presence of multiple autoimmune comorbidities. It also underscores the diagnostic value of tissue PLA2R testing and demonstrates the efficacy of early rituximab-based B-cell-directed therapy in achieving complete remission while avoiding corticosteroid exposure.
2025-10-30 | [Mixed type II cryoglobulinemiaassociated glomerulonephritis revealing an extragastric marginal zone lymphoma in the absence of viral infection: A rare case report from Bourges Hospital].
Type II mixed cryoglobulinemia is most commonly associated with chronic hepatitis C virus infection. The occurrence of marginal zone lymphoma as the underlying cause is rare, especially in the absence of gastric involvement. A 63-year-old woman with hypertension and hypothyroidism initially presented with transient purpura following a urinary tract infection. Two months later, she developed acute kidney injury, proteinuria (2.3 g/24 h), and microscopic hematuria. Laboratory tests showed type II mixed cryoglobulinemia (IgM κ + IgG) with hypocomplementemia. Viral serologies, including HCV, were negative. Renal biopsy revealed membranoproliferative glomerulonephritis with IgM and IgG deposits. Blood and bone marrow immunophenotyping confirmed an extragastric marginal zone lymphoma. The patient was treated with six cycles of rituximab-bendamustine. Complete remission was achieved: recovery of renal function (creatinine 84 μmol/L at 12 months), resolution of proteinuria, improvement of anemia, and regression of splenomegaly. No relapse was observed after 18 months of follow-up. This case represents a particularly rare presentation of type II mixed cryoglobulinemia revealing an extragastric marginal zone lymphoma in the absence of viral infection or gastric involvement. It contributes to the sparse literature on this uncommon association. Treatment with rituximab-bendamustine appears to be effective.
2024-09-12 | Defective thyroid hormone transport to the brain leads to astroglial alterations.
Allan-Herndon-Dudley syndrome (AHDS) is a rare X-linked disorder that causes severe neurological damage, for which there is no effective treatment. AHDS is due to inactivating mutations in the thyroid hormone transporter MCT8 that impair the entry of thyroid hormones into the brain, resulting in cerebral hypothyroidism. However, the pathophysiology of AHDS is still not fully understood and this is essential to develop therapeutic strategies. Based on evidence suggesting that thyroid hormone deficit leads to alterations in astroglial cells, including gliosis, in this work, we have evaluated astroglial impairments in MCT8 deficiency by means of magnetic resonance imaging, histological, ultrastructural, and immunohistochemical techniques, and by mining available RNA sequencing outputs. Apparent diffusion coefficient (ADC) imaging values obtained from magnetic resonance imaging showed changes indicative of alterations in brain cytoarchitecture in MCT8-deficient patients (n = 11) compared to control subjects (n = 11). Astroglial alterations were confirmed by immunohistochemistry against astroglial markers in autopsy brain samples of an 11-year-old and a 30th gestational week MCT8-deficient subjects in comparison to brain samples from control subjects at similar ages. These findings were validated and further explored in a mouse model of AHDS. Our findings confirm changes in all the astroglial populations of the cerebral cortex in MCT8 deficiency that impact astrocytic metabolic and mitochondrial cellular respiration functions. These impairments arise early in brain development and persist at adult stages, revealing an abnormal distribution, density, morphology of cortical astrocytes, along with altered transcriptome, compatible with an astrogliosis-like phenotype at adult stages. We conclude that astrocytes are potential novel therapeutic targets in AHDS, and we propose ADC imaging as a tool to monitor the progression of neurological impairments and potential effects of treatments in MCT8 deficiency.
2024-07-15 | Large-scale whole-exome sequencing analyses identified protein-coding variants associated with immune-mediated diseases in 350,770 adults.
The genetic contribution of protein-coding variants to immune-mediated diseases (IMDs) remains underexplored. Through whole exome sequencing of 40 IMDs in 350,770 UK Biobank participants, we identified 162 unique genes in 35 IMDs, among which 124 were novel genes. Several genes, including FLG which is associated with atopic dermatitis and asthma, showed converging evidence from both rare and common variants. 91 genes exerted significant effects on longitudinal outcomes (interquartile range of Hazard Ratio: 1.12-5.89). Mendelian randomization identified five causal genes, of which four were approved drug targets (CDSN, DDR1, LTA, and IL18BP). Proteomic analysis indicated that mutations associated with specific IMDs might also affect protein expression in other IMDs. For example, DXO (celiac disease-related gene) and PSMB9 (alopecia areata-related gene) could modulate CDSN (autoimmune hypothyroidism-, psoriasis-, asthma-, and Graves' disease-related gene) expression. Identified genes predominantly impact immune and biochemical processes, and can be clustered into pathways of immune-related, urate metabolism, and antigen processing. Our findings identified protein-coding variants which are the key to IMDs pathogenesis and provided new insights into tailored innovative therapies.
2024-02-07 | Superior Orbital Fissure Syndrome in the Setting of Relapsing Polychondritis with Concurrent Sjogren's Syndrome: A Case Report.
Ophthalmic manifestations of varying severity are often associated with systemic autoimmune conditions. Superior orbital fissure syndrome (SOFS) is a rare cranial neuropathy affecting nerves passing through the superior orbital fissure that causes a distinctive pattern of extraocular and pupillary findings. We report the coexistence of SOFS, relapsing polychondritis (RP) and Sjögren's syndrome (SS) in a 52-year-old female who presented with a past medical history of hypothyroidism, Raynaud's syndrome, and intermittent dry mouth and a 1-week history of worsening chemosis, proptosis, diplopia, and painful ophthalmoplegia. Following a comprehensive eye examination, the patient underwent a CT head with contrast, MRI of the orbit, lumbar puncture, and laboratory investigations. CT and MRI examination revealed inflammatory standing in periorbital subcutaneous soft tissues and bilateral exophthalmos with right intraconal fat stranding surrounding the intraorbital and intracanalicular segments of the nerve, respectively. Lumbar puncture and laboratory investigations revealed an elevation in inflammatory biomarkers, a negative infectious workup, and ruled in SS when considering her history alongside a positive Schirmer test. She was started on high-dose steroids, which led to significant improvement; however, treatment revealed type 2 diabetes, necessitating a faster steroid taper, during which there was a reoccurrence of scleritis and ophthalmoplegia, leading to the initiation of rituximab infusions. After completing rituximab course, she was transitioned back to steroid therapy and was successfully tapered without event. This case is notable for the rare coexistence of SOFS with RP/SS overlap syndrome and highlights the management of concurrent orbital inflammatory syndrome and autoimmune diseases.
oligonucleotides
2025-05-05 | LncRNA Dio3os regulates neighboring gene Dio3 and impacts osteogenesis in trans.
Consumptive hypothyroidism, a rare pediatric disorder, arises from aberrant Dio3 expression, which inactivates thyroid hormones and disrupts skeletal development. This study investigates the regulatory role of the long non-coding RNA Dio3os, which activates Dio3 in cis and suppresses osteoblast differentiation in trans. We focused on mouse Dio3os variant 203 and human variants 203 and 205. Chromatin accessibility and histone modification analyses revealed higher chromatin openness and active histone H3 modifications at the Dio3os promoter and exons 2 and 3, followed by increased RUNX2 binding with reduced histone H3 modifications during maturation. Dio3os expression is enhanced by HDAC1/2, HIF1a, and thyroid hormones, but repressed by BMP2, TGFb, Runx2, and Brg1. Overexpression of Dio3os upregulated Dio3 while downregulating osteogenic markers. CRISPR-mediated deletion of Dio3os exons or premature intronic polyadenylation suppressed Dio3 and restored osteogenic gene expression. RNA-seq and ATAC-seq confirmed enhanced thyroid hormone-responsive osteoblast gene activity in Dio3os-CRISPR-knockout cells. These findings reveal Dio3os as a key regulator of thyroid hormone metabolism and bone formation, presenting a novel target for treating skeletal abnormalities in early childhood hypothyroidism.
2021-10-20 | ZFP36L2 Role in Thyroid Functionality.
Thyroid hormone levels are usually genetically determined. Thyrocytes produce a unique set of enzymes that are dedicated to thyroid hormone synthesis. While thyroid transcriptional regulation is well-characterized, post-transcriptional mechanisms have been less investigated. Here, we describe the involvement of ZFP36L2, a protein that stimulates degradation of target mRNAs, in thyroid development and function, by in vivo and in vitro gene targeting in thyrocytes. Thyroid-specific Zfp36l2-/- females were hypothyroid, with reduced levels of circulating free Thyroxine (cfT4) and Triiodothyronine (cfT3). Their hypothyroidism was due to dyshormonogenesis, already evident one week after weaning, while thyroid development appeared normal. We observed decreases in several thyroid-specific transcripts and proteins, such as Nis and its transcriptional regulators (Pax8 and Nkx2.1), and increased apoptosis in Zfp36l2-/- thyroids. Nis, Pax8, and Nkx2.1 mRNAs were also reduced in Zfp36l2 knock-out thyrocytes in vitro (L2KO), in which we confirmed the increased apoptosis. Finally, in L2KO cells, we showed an altered response to TSH stimulation regarding both thyroid-specific gene expression and cell proliferation and survival. This result was supported by increases in P21/WAF1 and p-P38MAPK levels. Mechanistically, we confirmed Notch1 as a target of ZFP36L2 in the thyroid since its levels were increased in both in vitro and in vivo models. In both models, the levels of Id4 mRNA, a potential inhibitor of Pax8 activity, were increased. Overall, the data indicate that the regulation of mRNA stability by ZFP36L2 is a mechanism that controls the function and survival of thyrocytes.
2016-08-12 | JAG1 Loss-Of-Function Variations as a Novel Predisposing Event in the Pathogenesis of Congenital Thyroid Defects.
The pathogenesis of congenital hypothyroidism (CH) is still largely unexplained. We previously reported that perturbations of the Notch pathway and knockdown of the ligand jagged1 cause a hypothyroid phenotype in the zebrafish. Heterozygous JAG1 variants are known to account for Alagille syndrome type 1 (ALGS1), a rare multisystemic developmental disorder characterized by variable expressivity and penetrance. Verify the involvement of JAG1 variants in the pathogenesis of congenital thyroid defects and the frequency of unexplained hypothyroidism in a series of ALGS1 patients. A total of 21 young ALGS1 and 100 CH unrelated patients were recruited in academic and public hospitals. The JAG1 variants were studied in vitro and in the zebrafish. We report a previously unknown nonautoimmune hypothyroidism in 6/21 ALGS1 patients, 2 of them with thyroid hypoplasia. We found 2 JAG1 variants in the heterozygous state in 4/100 CH cases (3 with thyroid dysgenesis, 2 with cardiac malformations). Five out 7 JAG1 variants are new. Different bioassays demonstrate that the identified variants exhibit a variable loss of function. In zebrafish, the knock-down of jag1a/b expression causes a primary thyroid defect, and rescue experiments of the hypothyroid phenotype with wild-type or variant JAG1 transcripts support a role for JAG1 variations in the pathogenesis of the hypothyroid phenotype seen in CH and ALGS1 patients. clinical and experimental data indicate that ALGS1 patients have an increased risk of nonautoimmune hypothyroidism, and that variations in JAG1 gene can contribute to the pathogenesis of variable congenital thyroid defects, including CH.
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2022-11-01 | A CRISPR/Cas9-engineered avatar mouse model of monocarboxylate transporter 8 deficiency displays distinct neurological alterations.
Inactivating mutations in the specific thyroid hormone transporter monocarboxylate transporter 8 (MCT8) lead to an X-linked rare disease named MCT8 deficiency or Allan-Herndon-Dudley Syndrome. Patients exhibit a plethora of severe endocrine and neurological alterations, with no effective treatment for the neurological symptoms. An optimal mammalian model is essential to explore the pathological mechanisms and potential therapeutic approaches. Here we have generated by CRISPR/Cas9 an avatar mouse model for MCT8 deficiency with a point mutation found in two MCT8-deficient patients (P253L mice). We have predicted by in silico studies that this mutation alters the substrate binding pocket being the probable cause for impairing thyroid hormone transport. We have characterized the phenotype of MCT8-P253L mice and found endocrine alterations similar to those described in patients and in MCT8-deficient mice. Importantly, we detected brain hypothyroidism, structural and functional neurological alterations resembling the patient's neurological impairments. Thus, the P253L mouse provides a valuable model for studying the pathophysiology of MCT8 deficiency and in the future will allow to test therapeutic alternatives such as in vivo gene therapy and pharmacological chaperone therapy to improve the neurological impairments in MCT8 deficiency.
2022-08-30 | Whole-exome analysis of 177 pediatric patients with undiagnosed diseases.
Recently, whole-exome sequencing (WES) has been used for genetic diagnoses of patients who remain otherwise undiagnosed. WES was performed in 177 Japanese patients with undiagnosed conditions who were referred to the Tokai regional branch of the Initiative on Rare and Undiagnosed Diseases (IRUD) (TOKAI-IRUD). This study included only patients who had not previously received genome-wide testing. Review meetings with specialists in various medical fields were held to evaluate the genetic diagnosis in each case, which was based on the guidelines of the American College of Medical Genetics and Genomics. WES identified diagnostic single-nucleotide variants in 66 patients and copy number variants (CNVs) in 11 patients. Additionally, a patient was diagnosed with Angelman syndrome with a complex clinical phenotype upon detection of a paternally derived uniparental disomy (UPD) [upd(15)pat] wherein the patient carried a homozygous DUOX2 p.E520D variant in the UPD region. Functional analysis confirmed that this DUOX2 variant was a loss-of-function missense substitution and the primary cause of congenital hypothyroidism. A significantly higher proportion of genetic diagnoses was achieved compared to previous reports (44%, 78/177 vs. 24-35%, respectively), probably due to detailed discussions and the higher rate of CNV detection.
2017-10-04 | Central Hypothyroidism Due to a TRHR Mutation Causing Impaired Ligand Affinity and Transactivation of Gq.
Central congenital hypothyroidism (CCH) is an underdiagnosed disorder characterized by deficient production and bioactivity of thyroid-stimulating hormone (TSH) leading to low thyroid hormone synthesis. Thyrotropin-releasing hormone (TRH) receptor (TRHR) defects are rare recessive disorders usually associated with incidentally identified CCH and short stature in childhood. Clinical and genetic characterization of a consanguineous family of Roma origin with central hypothyroidism and identification of underlying molecular mechanisms. All family members were phenotyped with thyroid hormone profiles, pituitary magnetic resonance imaging, TRH tests, and dynamic tests for other pituitary hormones. Candidate TRH, TRHR, TSHB, and IGSF1 genes were screened for mutations. A mutant TRHR was characterized in vitro and by molecular modeling. A homozygous missense mutation in TRHR (c.392T > C; p.I131T) was identified in an 8-year-old boy with moderate hypothyroidism (TSH: 2.61 mIU/L, Normal: 0.27 to 4.2; free thyroxine: 9.52 pmol/L, Normal: 10.9 to 25.7) who was overweight (body mass index: 20.4 kg/m2, p91) but had normal stature (122 cm; -0.58 standard deviation). His mother, two brothers, and grandmother were heterozygous for the mutation with isolated hyperthyrotropinemia (TSH: 4.3 to 8 mIU/L). The I131T mutation, in TRHR intracellular loop 2, decreases TRH affinity and increases the half-maximal effective concentration for signaling. Modeling of TRHR-Gq complexes predicts that the mutation disrupts the interaction between receptor and a hydrophobic pocket formed by Gq. A unique missense TRHR defect identified in a consanguineous family is associated with central hypothyroidism in homozygotes and hyperthyrotropinemia in heterozygotes, suggesting compensatory elevation of TSH with reduced biopotency. The I131T mutation decreases TRH binding and TRHR-Gq coupling and signaling.
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Drug Discovery Landscape
1 orphan drug designation for Rare hypothyroidism, including 1 approved therapy.
1 orphan drug designation for Rare hypothyroidism, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
Liothyronine sodium injection [Triostat] | small molecules | FDA | Approved | SmithKline Beecham Pharmaceuticals |
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