Zac is a 13-year-old boy who presented with his parents to developmental-behavioral pediatrics seeking diagnostic clarity. He was born by vaginal delivery at full term after an uncomplicated pregnancy. Developmental milestones were met at typical ages until he was noted to have language delay and to be hyperactive and impulsive on entering preschool at age 4 years. Although he used some phrases in speech, he often used physical force to take toys from other children, rather than using words.On entering preschool at age 4 years, he was noted to have language delay (i.e., continued use of phrase speech only) and to be hyperactive and impulsive. An evaluation to determine eligibility for an Individualized Education Program (IEP) was completed and found him to have delays in cognition, receptive language, expressive language, social-emotional, and adaptive skills. His fine motor skills were in the low average range, and his gross motor skills were in the average range. He was admitted into an early childhood special education program, and aggressive behavior and hyperactivity decreased in the structured classroom.At age 7 years, Zac was re-evaluated by the school district and found to have moderate intellectual disability (ID). Chromosomal microarray analysis and testing for Fragile X syndrome were normal. He was noted to enjoy interacting with other children and adults, but his play was very immature (e.g., preference for cause/effect toys). He was able to respond appropriately when asked his name and age, but he also frequently demonstrated echolalia. He was also evaluated by his primary care physician and found to meet the criteria for attention-deficit/hyperactivity disorder, combined presentation (ADHD). Treatment with methylphenidate was initiated but discontinued after a brief time because of increased aggressive behaviors.Owing to continued significant tantrums, aggressive tendencies, and inability to communicate his basic needs, Zac was evaluated at a local Regional Center (statewide system for resources and access to services for individuals with developmental disabilities) at age 10 years and found to meet the criteria for autism spectrum disorder (ASD), and previous diagnosis of ID was confirmed. Zac received applied behavior analysis (ABA), but this was discontinued after 1 year because of a combination of a change in the insurance provider and parental perception that the therapy had not been beneficial.Zac became less hyperactive and energetic as he grew older. By the time Zac presented to the developmental-behavioral clinic at age 13 years, he was consistently using approximately 30 single words and was no longer combining words into phrases. He had a long latency in responding to verbal and nonverbal cues and seemed to be quite withdrawn. Physical examination revealed scoliosis and hand tremors while executing fine motor tasks. Seizures were not reported, but neuromotor regression was apparent from the examination and history. Laboratory studies including thyroid-stimulating hormone, free T4, creatine kinase, very-long-chain fatty acids, lactate, pyruvate, urine organic acids, and plasma amino acids were normal. Cranial magnetic resonance imaging demonstrated abnormal T2 hyperintensities in the periventricular and deep cerebral white matter and peridentate cerebellar white matter, consistent with a "tigroid" pattern seen in metachromatic leukodystrophy (MLD) and other white matter neurodegenerative diseases. Arylsulfatase A mutation was detected with an expanded ID/ASD panel, and leukocyte arylsulfatase activity was low, confirming the diagnosis of juvenile-onset MLD.Are there behavioral markers and/or historical caveats that clinicians can use to distinguish between ASD/ID with coexisting ADHD and a neurodegenerative disorder with an insidious onset of regression?

Hypothyroidism is a systemic hypometabolic syndrome caused by the thyroxine resistance or a reduction in its extent. It is an endocrinopathy secondary to gestational diabetes and occurs usually without significant symptoms. This study explored the effect of bisphenol A (BPA)-mediated retinol-binding protein 4 (RBP-4) on pregnancy outcomes in a nonobese pregnant female with subclinical hypothyroidism. Three hundred nonobese pregnant females who had that established pregnancy files and had regular obstetric examinations from January 2021 to March 2022 were enrolled and classified with 100 cases in each group as early pregnancy (6-12 weeks of gestation), second-trimester (13-24 weeks of gestation), and third-trimester groups (25-36 weeks of gestation). Thirty pregnant women with subclinical hypothyroidism were selected as subjects, and another thirty pregnant women with normal thyroid function were selected as the normal control group. Thyroid function (thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free T4 (FT4), and thyroid peroxidase antibody (TPO-Ab)) was measured by immunoelectrochemiluminescence. The level of BPA in urine was determined by solid-phase extraction high-performance liquid chromatography-tandem mass spectrometry. Serum RBP4 levels were determined by enzyme-linked immunosorbent assay. The level of TSH in the third-trimester group was higher than that in the first- and second-trimester groups, while the levels of FT3, FT4, and TPO-Ab were lower than those in the other two groups (P < 0.05). TSH in the second-trimester group was higher than that in the first-trimester group, while FT3, FT4, and TPO-Ab levels were lower than those in the first-trimester group (P < 0.05). The levels of BPA and RBP4 in gestational diabetes mellitus and hypertension were higher than those in the nongestational period, and the levels of BPA and RBP4 in gestational intrahepatic cholestasis and anemia were higher than those in the nongestational period, and the levels of BPA and RBP4 in preterm delivery were higher than those in nongestational period (P < 0.05). Also, the level of urinary BPA in the hypothyroidism group was higher than that in the normal control group (P < 0.05) and the level of serum RBP4 in the hypothyroidism group was higher than that in the normal control group (P < 0.05). According to multivariate logistic regression analysis, age ≥30 years and the ascending BPA and RBP4 were risk factors for subclinical hypothyroidism during pregnancy in the nonobese female. BPA and RBP-4 are closely related to the pregnancy outcome of nonobese subclinical hypothyroidism in the pregnant female. The degree of BPA and RBP-4 in adverse pregnancy outcomes is increased, which is the risk factor for nonobese subclinical hypothyroidism.

Gestational hypothyroidism can impair development, cognition, and mood. Here, we tested whether multisensory stimulation (MS) improves the phenotype of rats born to surgically thyroidectomized (Tx) dams suboptimally treated with LT4. 8-week-old female Tx Wistar rats were kept on daily LT4 (0.7 µg/100 g body weight) dosed by gavage (serum TSH and T4 levels indicated moderate hypothyroidism) and 3 weeks later placed for breeding. MS of the litter started at age 60 days and lasted for 8 weeks. It consisted of twice per week of physical, cognitive, sensorial, and food stimuli. The offspring were assessed before and after MS for standardized tests of locomotor activity, cognition, and mood. Gestational hypothyroidism resulted in reduced litter size and increased offspring mortality. The pups exhibited delayed physical development, impairment of short- and long-term memory, and anxiety- and depressive-like behaviors. Nonetheless, ambulatory activity, social memory, and social preference were not affected by gestational hypothyroidism. MS restored short-term memory and anxiety while improving depressive like-behaviors. MS did not improve long-term memory. MS also did not modify the performance of control litter born to intact dams. We conclude that cognition and mood impairments caused by moderate gestational hypothyroidism were reversed or minimized in rats through MS. Further studies should define the molecular mechanisms involved.

Graves' disease can have multiple cardiac manifestations. A rare complication is that of severe mitral regurgitation secondary to mitral valve chordae rupture, due to both compromise of valve integrity by deposition of glycosaminoglycans and the hemodynamic stresses of thyrotoxicosis. Pregnancy, with its related hemodynamic changes, is another setting in which mitral valve chordae rupture has occasionally been documented. We present a unique case of a 36-year-old female with uncontrolled Graves' disease who presented during pregnancy at 13 weeks gestation with atrial flutter and features of congestive heart failure. Echocardiogram found severe mitral regurgitation secondary to a ruptured mitral chord. She was treated conservatively with diuresis and ultimately delivered her baby without complication at 28 weeks when she had preterm premature rupture of membranes. She is currently on methimazole and propranolol and pending definitive management of her Graves' disease. This represents not only a rare cardiac complication in a patient with Graves' disease but also is the first in the literature, to our knowledge, which describes this complication in a pregnant patient with Graves' disease.

Perinatal hypothyroidism impairs cerebellar organogenesis and results in motor coordination defects. The thyroid hormone receptor binds to corepressor complexes containing histone deacetylase (HDAC) 3 in the absence of ligands and acts as a transcriptional repressor. Although histone acetylation status is strongly correlated with transcriptional regulation, its role in cerebellar development remains largely unknown. We aimed to study whether the cerebellar developmental defects induced by perinatal hypothyroidism can be rescued by treatment with a specific HDAC3 inhibitor, RGFP966. Motor coordination was analyzed using three behavioral tests. The cerebella were subjected to RT-qPCR and chromatin immunoprecipitation assays for acetylated histone H3. The treatment with RGFP966 partially reversed the cerebellar morphological defects in perinatal hypothyroid mice. These findings were associated with the alleviation of motor coordination defects in these mice. In addition, the RGFP966 administration increased the mRNA levels of cerebellar thyroid hormone-responsive genes. These increases were accompanied by augmented histone acetylation status at these gene loci. These findings indicate that HDAC3 plays an important role in the cerebellar developmental defects induced by perinatal hypothyroidism. The HDAC3 inhibitor might serve as a novel therapeutic agent for hypothyroidism-induced cerebellar defects by acetylating histone tails and stimulating transcription at thyroid hormone-responsive gene loci.

Phthalates are a class of environmental endocrine disruptors. Previous studies have demonstrated that phthalate exposure can affect thyroid function; however, limited studies have assessed the associations between phthalate exposure and thyroid function, especially thyroid autoimmunity in pregnant women during the first trimester. We recruited participants from a cohort of pregnant women in Beijing, China, and collected urine samples to measure ten phthalate metabolites, serum samples to measure free thyroxine (FT4), thyroid-stimulating hormone (TSH), thyroid peroxidase antibody (TPOAb) during the first trimester. We included 325 pregnant women without thyroid diseases or dysfunction in this study. Associations between phthalate metabolites and thyroid function parameters were assessed with the Bayesian kernel machine regression (BKMR) model, multiple linear regression model, and restricted cubic spline. In the BKMR model analysis, compared to the 50th percentile, total urinary phthalate metabolites levels were negatively associated with serum TPOAb levels when phthalate metabolites were at or below the 40th percentile. Stratifying by body mass index, total urinary phthalate metabolites levels were negatively associated with serum TPOAb levels in normal weight women when phthalate metabolites were at or below the 45th percentile. However, total urinary phthalate metabolites levels were positively associated with serum TPOAb levels in underweight women when phthalate metabolites were at or below the 30th percentile. In restricted cubic spline analysis, L-shaped nonlinear associations of mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), di-(2-ethylhexyl) phthalate (ΣDEHP), and inverted S-shaped nonlinear association of mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP) with TPOAb were observed. In conclusion, our findings suggest that phthalate exposure may affect thyroid autoimmunity in underweight pregnant women during early pregnancy, and the potential effects of phthalate exposure on thyroid autoimmunity may be nonlinear.

Lithium-salts stand on the first line of therapy for the management of specific psychiatric conditions, mainly bipolar mood disorder. It is also known to protect the brain against neurodegenerative processes such as Alzheimer's disease. Despite the mentioned merits, recent studies have revealed that high dose or prolonged lithium intake deteriorate the function of multiple key organs including heart, ovaries, thyroid gland and kidneys. Mechanistically, both positive and negative effects of lithium are mediated through methylation of β-catenin nuclear-binding proteins which is potentiated by lithium-induced inhibition of GSK-3 or inositol monophosphatase. The current study briefly reviews the recent experimental data on lithium therapy considering both positive (i.e., neuroprotective) and negative aspects. In this regard, the question is that whether doses of lithium administered in experimental research are comparable with the therapeutic doses, as currently prescribed in clinical practice. It should be noted that the experimental data on animal studies, as widely reviewed here, could not be directly generalized to clinic. This is mainly because lithium doses applied in animal models are usually higher than therapeutic doses, however, there are evidence indicating that even animal to human translated doses of lithium, cause serious complications and this has been reported by meta-analyses on human studies. Therefore, we suggest the clinicians to use lithium-salts with precaution particularly in pregnancy and precisely adjust lithium concentration considering the patient's general health status to avoid lithium toxicity. Indeed, alternative approaches are recommended when the subject is pregnant, prolonged therapy is required or specific organ dysfunction is diagnosed.

Hashimoto thyroiditis and Graves' disease are autoimmune thyroid diseases which occur much more frequently in women than in men. Estrogen receptors are found in the thyroid gland and can modulate the gland's function. Digit ratio (2D:4D) is thought to be a negative correlate of prenatal testosterone and a positive correlate of prenatal estrogen. This study aimed to examine a relationship between right and left 2D:4D in women with Hashimoto thyroiditis and Graves' disease. The cross-sectional study included 106 women with autoimmune thyroid disease: 73 women diagnosed with Hashimoto thyroiditis and 33 women with Graves' disease, together with 70 healthy women as controls. Second and fourth digit length, weight, height were measured directly, and 2D:4D and BMI were calculated. Compared to controls, right and left 2D:4D were significantly higher in women with Hashimoto thyroiditis and lower in women with Graves' disease, the effects were higher for right 2D:4D. The mean length of right 4D was significantly lower in the examined women with Hashimoto thyroiditis than in Graves' disease. Higher right and left 2D:4D in women with Hashimoto thyroiditis suggests that prenatal exposure to high levels of estrogens relative to testosterone may play a role in the development of this disease. Lower right and left 2D:4D in women with Graves' disease suggest a role of high prenatal androgens relative to estrogens in Graves' disease pathogenesis.

Human gestation leads to a number of physiological alterations which peak at the development of placentta known for, among many other functions, being a transient but highly potent endocrine organ. Hormonal activity of placenta is marked by its ability to continuously produce and secrete high levels of progesterone. Progesterone guards the well-being of the fetoplacental unit throughout the gestation and one of the proposed mechanisms of this principle involves the development of local and systemic immune tolerance mainly due to impediment of CD4+ lymphocyte activation. However, though these alterations are present and well-established, autoimmunity is not entirely rare and a wide spectrum of diseases can continue, or develop de novo, throughout the gestation or even after the delivery. Up-to-date data supports the existence of a relationship between the clinical course of chosen autoimmune diseases and levels of circulating sex steroids. The most common autoimmune endocrinopathies in pregnant women are Hashimoto's disease, Graves' disease, and, more rarely, primary adrenal insufficiency in the form of Addison's disease. Gestation can influence the clinical course of these endocrinopathies in patients who were diagnosed before conception. Multiple particles, like TSH-receptor stimulating antibodies, thyroid hormones, glucocorticoids, and anti-thyroid medications, can cross the placental barrier and evoke biological action in fetal tissues. Thyroid pathology in the form of postpartum thyroiditis is particularly prevalent in patients with positive anti-thyroperoxidase and anti-thyroglobulin antibodies. Certain populations are more at risk of developing numerous gestational complications and require regular follow-up. In our paper, we would like to address physiological, physiopathological, and clinical aspects of endocrine autoimmunity throughout human gestation, as well as special circumstances to consider in pregnant women.

Normal thyroid status throughout pregnancy is important for both maternal and fetal health. Despite the bulk of contemporary research honing on thyroid function in gestation and the relevant disorders, there are still gaps in our current knowledge about the etiology and treatment of thyroid diseases in pregnant women.

Hydatidiform mole is a malignant entity included in the gestational trophoblastic diseases. It usually produces pregnancy hormones such as beta-human chorionic gonadotropin (β-hCG), which in turn stimulates endogenous thyroid hormone production. We report the case of a high-risk complete invasive hydatidiform mole with pulmonary metastasis and associated paraneoplastic syndrome. The patient is a 30-year-old woman who presented symptoms of pregnancy and metrorrhagia. A uterine mass was detected. Urine β-hCG was found negative. In serum, 2,662,000 mIU/mL (normal range: <5) was found, together with parameters of severe hyperthyroidism. The patient underwent uterine curettage with diagnostic and therapeutic means. At that precise moment, her pregnancy-like symptoms worsened and she developed restlessness, tachycardia, diaphoresis, dyspnea at rest, and peripheral edema. A scan showed bilateral pulmonary nodules suggestive of metastasis, acute pulmonary edema, and bilateral pleural effusion without signs of pulmonary thromboembolism. At that time, she presented a free T4 of 2.34 ng/dL (normal range: 0.8-1.8 ng/dL), causing a thyroid storm with secondary cardiac dysfunction. The patient was treated with corticosteroid therapy to decrease peripheral conversion of thyroid hormone T4 to active T3. Her symptoms remitted within 8 h. After 48 h, T4 level was 1.2 ng/dL while serum β-hCG was 80,000 mIU/mL, with a positive urine result. The change in the urine analysis is due to the "hook effect" of the reactive test. An effective chemotherapy treatment was started according to the EMA-CO scheme, remaining free of disease at present. Knowing paraneoplastic syndromes is necessary to achieve the best clinical management and to start treatment early.

Hyperthyroidism is characterized by an increase in the synthesis and secretion of thyroid hormones in the thyroid gland, and the most common cause of overproduction of thyroid hormones is Graves' disease (GD). Long-term disease models of hyperthyroidism have been established. In general, methods to induce GD include transfection of fibroblasts, injecting plasmids or adenovirus containing thyroid stimulating hormone receptor (TSHR) or TSHR subunit, and exogenous artificial thyroid hormone supplementation. Fortunately, in mouse studies, novel treatments for GD and Graves' orbitopathy (GO) were discovered. It has been reported that prophylactic administration of TSHR A subunit protein in genetically susceptible individuals could induce immune tolerance and provide protection for the future development of GD. Biologically active monoclonal antibody against intracellular adhesion molecule-1 (ICAM-1 mAb) and siRNA targeting TSHR can also be used to treat GD. Moreover, new potential therapeutic targets have been identified in GO mouse models, and these targets could present novel therapeutic approaches. Besides, human placental mesenchymal stem cells (hPMSCs) into the orbit, fucoxanthin and icariin may be new alternative therapies that could be used in addition to the existing drugs, although further research is needed.

Thyroid diseases in pregnant and lactating women may result in adverse outcomes for both mothers and infants. A reference range for thyroid function is required in different areas; however, few studies on the gestational change or reference ranges of thyrotropin (TSH) and free thyroxine (FT4) concentrations for Japanese pregnant women have been reported. To establish the gestational trimester-specific reference ranges of serum TSH and FT4 concentrations, our previously published data on 481 pregnant women with the mean age of 30.8 years who provided serum samples as early as gestational week (GW) 6 was compiled by using their percentile values. The overall median urinary iodine concentration (UIC) during pregnancy was 201 μg/L suggesting adequate iodine intake. The prevalence of positive serum thyroid autoantibody (ThAb), i.e., antithyroid peroxidase antibody (TPOAb) and antithyroglobulin antibody (TgAb), was 11.4%. The reference ranges (2.5-97.5th percentile) of serum TSH and FT4 concentration calculated for samples with negative TgAb and TPOAb were 0.04-6.06 mIU/L in the first trimester (T1), 0.31-3.11 mIU/L in the second trimester (T2) and 0.48-3.93 mIU/L in the third trimester (T3) for TSH, and 1.10-1.87 ng/dL (T1), 0.76-1.56 ng/dL (T2) and 0.76-1.14 ng/dL (T3) for FT4. Compared to published data around the world in the 2017 American Thyroid Association (ATA) guideline, both the upper and lower limits of our TSH and FT4 reference ranges in the first trimester were higher than those in other countries. Further research is necessary in larger samples.

Multiple sclerosis (MS) is an autoimmune disease characterized by a robust inflammatory response against myelin sheath antigens, which causes astrocyte and microglial activation and demyelination of the central nervous system (CNS). Multiple genetic predispositions and environmental factors are known to influence the immune response in autoimmune diseases, such as MS, and in the experimental autoimmune encephalomyelitis (EAE) model. Although the predisposition to suffer from MS seems to be a multifactorial process, a highly sensitive period is pregnancy due to factors that alter the development and differentiation of the CNS and the immune system, which increases the offspring's susceptibility to develop MS. In this regard, there is evidence that thyroid hormone deficiency during gestation, such as hypothyroidism or hypothyroxinemia, may increase susceptibility to autoimmune diseases such as MS. In this review, we discuss the relevance of the gestational period for the development of MS in adulthood.