Diagnostic and therapeutic challenges in the Allan-Herndon-Dudley Syndrome

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.</p

Diagnostic and therapeutic challenges in the Allan-Herndon-Dudley Syndrome

Thyroid hormone (TH) is important for normal brain development. The TH transporter protein monocarboxylate transporter 8 (MCT8) is crucial to maintain adequate TH levels in the brain during development and throughout life. Mutations in MCT8 result in the Allan-Herndon-Dudley syndrome (AHDS), which is characterized by a severe delay in neurocognitive development, combined with abnormal serum thyroid function tests (TFTs). The combination of an increased (F)T3 and decreased (F)T4 and rT3 serum levels are characteristic for the presence of AHDS in male patients with moderate to severe delay in neurocognitive development. Here, we provide an overview of current insights, challenges and pitfalls in the diagnosis and management of patients with AHDS.</p

Parent perspectives on complex needs in patients with MCT8 deficiency: an international, prospective, registry study

Context: Monocarboxylate transporter 8 (MCT8) deficiency is a rare neurodevelopmental and metabolic disorder, with daily care posing a heavy burden on caregivers. A comprehensive overview of these complex needs and daily care challenges is lacking. Design: We established an international prospective registry to systemically capture data from parents and physicians caring for patients with MCT8 deficiency. Parent-reported data on complex needs and daily care challenges were extracted. Results: Between July 17, 2018, and May 16, 2022, 51 patients were registered. Difficulties in daily life care were mostly related to feeding and nutritional status (17/33 patients), limited motor skills (12/33 patients), and sleeping (11/33 patients). Dietary advice was provided for 11/36 patients. Two of 32 patients were under care of a cardiologist. Common difficulties in the diagnostic trajectory included late diagnosis (20/35 patients) and visiting a multitude of specialists (15/35 patients). Median diagnostic delay was significantly shorter in patients born in or after 2017 vs before 2017 (8 vs 19 months, P &lt; .0001). Conclusions: Feeding and sleeping problems and limited motor skills mostly contribute to difficulties in daily care. The majority of patients did not receive professional dietary advice, although being underweight is a key disease feature, strongly linked with poor survival. Despite sudden death being a prominent cause of death, potentially related to the cardiovascular abnormalities frequently observed, patients were hardly seen by cardiologists. These findings can directly improve patient-centered multidisciplinary care and define patient-centered outcome measures for intervention studies in patients with MCT8 deficiency.</p

Rotating traversable wormholes

The general form of a stationary, axially symmetric traversable wormhole is discussed. This provides an explicit class of rotating wormholes that generalize the static, spherically symmetric ones first considered by Morris and Thorne. In agreement with general analyses, it is verified that such a wormhole generically violates the null energy condition at the throat. However, for suitable model wormholes, there can be classes of geodesics falling through it which do not encounter any energy-condition-violating matter. The possible presence of an ergoregion surrounding the throat is also noted.Comment: 15 pages, harvmac; 1 figure in PicTeX; minor changes; to appear in Phys. Rev.

Insight Into Molecular Determinants of T3 vs T4 Recognition From Mutations in Thyroid Hormone Receptor α and β.

CONTEXT: The two major forms of circulating thyroid hormones (THs) are T3 and T4. T3 is regarded as the biologically active hormone because it binds to TH receptors (TRs) with greater affinity than T4. However, it is currently unclear what structural mechanisms underlie this difference in affinity. OBJECTIVE: Prompted by the identification of a novel M256T mutation in a resistance to TH (RTH)α patient, we investigated Met256 in TRα1 and the corresponding residue (Met310) in TRβ1, residues previously predicted by crystallographic studies in discrimination of T3 vs T4. METHODS: Clinical characterization of the RTHα patient and molecular studies (in silico protein modeling, radioligand binding, transactivation, and receptor-cofactor studies) were performed. RESULTS: Structural modeling of the TRα1-M256T mutant showed that distortion of the hydrophobic niche to accommodate the outer ring of ligand was more pronounced for T3 than T4, suggesting that this substitution has little impact on the affinity for T4. In agreement with the model, TRα1-M256T selectively reduced the affinity for T3. Also, unlike other naturally occurring TRα mutations, TRα1-M256T had a differential impact on T3- vs T4-dependent transcriptional activation. TRα1-M256A and TRβ1-M310T mutants exhibited similar discordance for T3 vs T4. CONCLUSIONS: Met256-TRα1/Met310-TRβ1 strongly potentiates the affinity of TRs for T3, thereby largely determining that T3 is the bioactive hormone rather than T4. These observations provide insight into the molecular basis for underlying the different affinity of TRs for T3 vs T4, delineating a fundamental principle of TH signaling

Preferences of patients, clinicians, and healthy controls for the management of a Bethesda III thyroid nodule

Background: Active surveillance is propagated as an alternative for hemithyroidectomy in the management of Bethesda III thyroid nodules. Methods: A cross-sectional survey questioned respondents on their willingness to accept risks related to active surveillance and hemithyroidectomy. Results: In case of active surveillance, respondents (129 patients, 46 clinicians, and 66 healthy controls) were willing to accept a risk of 10%–15% for thyroid cancer and 15% for needing more extensive surgery in the future. Respondents were willing to accept a risk of 22.5%–30% for hypothyroidism after hemithyroidectomy. Patients and controls were willing to accept a higher risk on permanent voice changes compared with clinicians (10% vs. 3%, p < 0.001). Conclusion: Real-life risks associated which active surveillance and hemithyroidectomy for Bethesda III nodules are equivalent or less than the risks people are willing to accept. Clinicians accepted less risk for permanent voice changes

Development of a pediatric differentiated thyroid carcinoma registry within the EuRRECa project: rationale and protocol

Registry; Thyroid carcinoma; ChildhoodRegistro; Carcinoma de tiroides; InfanciaRegistre; Carcinoma de tiroides; InfànciaBackground Although differentiated thyroid carcinoma (DTC) is the most frequent endocrine pediatric cancer, it is rare in childhood and adolescence. While tumor persistence and recurrence are not uncommon, mortality remains extremely low. Complications of treatment are however reported in up to 48% of the survivors. Due to the rarity of the disease, current treatment guidelines are predominantly based on the results of small observational retrospective studies and extrapolations from results in adult patients. In order to develop more personalized treatment and follow-up strategies (aiming to reduce complication rates), there is an unmet need for uniform international prospective data collection and clinical trials. Methods and analysis The European pediatric thyroid carcinoma registry aims to collect clinical data for all patients ≤18 years of age with a confirmed diagnosis of DTC who have been diagnosed, assessed, or treated at a participating site. This registry will be a component of the wider European Registries for Rare Endocrine Conditions project which has close links to Endo-ERN, the European Reference Network for Rare Endocrine Conditions. A multidisciplinary expert working group was formed to develop a minimal dataset comprising information regarding demographic data, diagnosis, treatment, and outcome. We constructed an umbrella-type registry, with a detailed basic dataset. In the future, this may provide the opportunity for research teams to integrate clinical research questions. Ethics and dissemination Written informed consent will be obtained from all participants and/or their parents/guardians. Summaries and descriptive analyses of the registry will be disseminated via conference presentations and peer-reviewed publications.SFA and ALP are supported by the European Union’s Health Programme (2014–2020) on the EuRRECa project ‘777215/EuRRECa’ and the EuRR-Bone project ‘946831/EuRR-Bone’. The EuRRECa project is also grateful to the European Society of Endocrinology and the European Society for Paediatric Endocrinology for funding support