Delayed Postnatal Growth and Anterior Pituitary Development in Growth-Retarded (grt) Female Mice.

Growth-retarded (grt) mice display primary congenital hypothyroidism due to the hyporesponsiveness of their thyroid glands to thyroid-stimulating hormone (TSH). We examined somatic growth, anterior pituitary development, and hormonal profiles in female grt mice and normal ones. Although growth in grt females was suppressed 2 weeks after birth, the measured growth parameters and organ weights gradually increased and finally reached close to the normal levels. Grt mice exhibited delayed eye and vaginal openings and remained in a state of persistent diestrus thereafter, plasma estrogen levels being lower than those in normal mice. Grt mice that received normal-donor thyroids showed accelerated growth and their body weights increased up to the sham-normal levels, indicating the importance of early thyroid hormone supplementation. In the anterior pituitary, there were fewer growth hormone (GH) and prolactin (PRL) cells in grt mice than in normal mice as examined at 12 weeks after birth, but the numbers of these cells did not differ from those in normal mice after 24 weeks. Grt mice had more TSH cells than normal mice until 48 weeks. Plasma GH levels in grt mice were lower than those in normal mice at 2 weeks, but did not differ substantially after 5 weeks. Compared with normal mice, grt mice had significantly lower plasma PRL and thyroxine levels, but notably higher TSH levels until 48 weeks. These findings indicate that thyroid hormone deficiency in grt mice causes delayed development and growth, and inappropriate development of GH, PRL and TSH cells, followed by the abnormal secretion of hormones by these pituitary cells.

Thyroid Hormone in the Pathogenesis of Congenital Intestinal Dysganglionosis.

INTRODUCTION: The objective of this study is to investigate the role of thyroid hormone (TH) in the pathogenesis of intestinal dysganglionosis (ID). METHODS: A zebrafish model of congenital hypothyroidism (CH) was created by exposing the larvae to the 6-propyl-2-thiouracil (PTU). The enteric neurons were labeled with anti-HuC/D antibodies. The number of enteric neurons was counted. The larval intestine was dissociated and stained with anti-p75 and anti-α4 integrin antibodies. Mitosis and apoptosis of the p75+ α4 integrin+ enteric neural crest cells (ENCCs) were studied using flow cytometry. Intestinal motility was studied by analyzing the transit of fluorescent tracers. RESULTS: PTU (25 mg/L) significantly reduced TH production at 6- and 9-days post fertilization without changing the body length, body weight, and intestinal length of the larvae. Furthermore, PTU inhibited mitosis of ENCCs and reduced the number of enteric neurons throughout the larval zebrafish intestine. Importantly, PTU inhibited intestinal transit of fluorescent tracers. Finally, thyroxine supplementation restored ENCC mitosis, increased the number of enteric neurons, and recovered intestinal motility in the PTU-treated larvae. CONCLUSIONS: PTU inhibited TH production, reduced the number of enteric neurons, impaired intestinal motility, and impeded ENCC mitosis in zebrafish, suggesting a possible role of CH in the pathogenesis of ID.

Congenital Feline Hypothyroidism With Partially Erupted Adult Dentition in a 10-Month-Old Male Neutered Domestic Shorthair Cat: A Case Report.

Congenital feline hypothyroidism was diagnosed in a 10-month-old kitten. The kitten appeared to have disproportionate dwarfism, with the clinical signs of incompletely erupted permanent dentition covered by thickened gingival tissue, short stature, a broad, flattened face, short neck, pendulous abdomen, kitten-like hair coat, and goiter. Hypothyroidism was confirmed with baseline T4, freeT4, and thyroid-stimulating hormone testing. The kitten was treated with thyroid hormone supplementation and monitored. The kitten appeared clinically like a normal healthy cat at 22 months of age on thyroid supplementation.

Heterogeneity of lung disease associated with NK2 homeobox 1 mutations.

We retrospectively studied the clinical presentation, treatment modalities and outcome in 16 patients with heterozygous NKX2-1 mutation associated with chronic lung disease. Twelve different NKX2-1 mutations, including 4 novel mutations, were identified in the 16 patients. Nine patients presented with brain-lung-thyroid syndrome, 3 had neurological and lung symptoms and 4 had only pulmonary symptoms. Ten patients had neonatal respiratory distress, and 6 of them developed infiltrative lung disease (ILD). The other patients were diagnosed with ILD in childhood (n = 3) or in adulthood (n = 3). The median age at diagnosis was 36 months (IQ 3.5-95). Patient testing included HRCT (n = 13), BALF analysis (n = 6), lung biopsies (n = 3) and lung function tests (n = 6). Six patients required supplemental oxygen support with a median duration of 18 months (IQ 2.5-29). All symptomatic ILD patients (n = 12) benefited from a treatment consisting of steroids, azithromycin (n = 9), and/or hydroxychloroquine (n = 4). The median follow-up was 36 months (IQ 24-71.5). One patient died of respiratory failure at 18 months and another is waiting for lung transplantation. In summary, the initial diagnosis was based on clinical presentation and radiological features, but the presentation was heterogeneous. Definitive diagnosis required genetic analysis, which should be performed, even in absence of neurological or thyroid symptoms.

Neuroplastic effects of music lessons on hippocampal volume in children with congenital hypothyroidism.

Children with congenital hypothyroidism (CH) who experience a neonatal thyroid hormone deficiency have reduced hippocampal volumes compared with healthy controls. Interestingly, evidence suggests that musical training can contribute to structural plasticity in a number of brain areas, including the hippocampus. Therefore, we investigated whether taking music lessons could ameliorate the volumetric reductions of the hippocampus in children with CH. Left and right hippocampal volumes were measured in four groups of children: children with CH with and without music lessons, and healthy controls with and without music lessons. We found that the volume of the right hippocampus was comparable between children with CH who had taken music lessons and the healthy controls. Children with CH who had not taken music lessons had reduced hippocampal volumes compared with the other three groups. These results suggest that music lessons may induce structural neuroplasticity in children with atypical hippocampal development because of early thyroid hormone deficiencies.

Brain derived neurotrophic factor and oxidative stress index in pups with developmental hypothyroidism: neuroprotective effects of selenium.

Thyroid hormones (THs) are crucial for growth and development and particularly brain development. The present study was carried out to investigate the brain derived neurotrophic factor (BDNF) and Oxidative stress index (OSI) in the brain of pups born to dams with methimazole (MMI) induced hypothyroidism. Also, to elucidate the effectiveness of selenium (Se) in ameliorating the brain damaging effects induced by maternal hypothyroidism. Our results reveled that plasma free T3 (FT3), free T4 (FT4), growth hormone (GH) were significantly decreased while plasma thyroid stimulating hormone (TSH) was significantly increased in the pups. BDNF level significantly decreased while OSI significantly increased in both the hippocampus and cerebellum in pups born to hypothyroid dams. Se supplementation significantly alleviated the levels of these parameters. The biochemical modifications were confirmed histologically with the abnormal development of the hippocampus and cerebellum and partial reversal of these effects with Se supplementation. We concluded that reduced hippocampal and cerebellar BDNF levels and increment of oxidative stress during early development may contribute to the adverse neurodevelopmental effects of hypothyroidism during pregnancy. Also, Se is an important neuroprotective element that may be used as a dietary supplement against brain damage induced by hypothyroidism.

A thyroid peroxidase (TPO) mutation in dogs reveals a canid-specific gene structure.

Congenital hypothyroidism with goiter (CHG) occurring as an autosomal recessive disorder is typically due to a defect of thyroid hormone synthesis (aka dyshormonogenesis). Thyroid peroxidase (TPO) is a multifunctional, heme-containing enzyme whose activity is required, and several inactivating TPO mutations causing CHG in humans and dogs have been described. Recently, two half-sib Spanish water dog (SWD) pups were diagnosed with CHG based on clinical signs, endocrine testing, and thyroid histology. TPO enzyme activity was absent, and immuno-cross-reactive TPO was undetectable in affected-dog thyroid tissue. A single guanosine insertion was observed in the first exon of the affected-dog TPO cDNA at a site not previously thought to be within the coding sequence. The insertion allele segregated with the deduced disease allele in the SWD breed and was not observed in unrelated dogs of various breeds. Comparison of the insertion site (an 8-nt poly-G tract) with the orthologous sequences of other mammalian reference genomes revealed that the octa-G tract obliterated the intron 1 splice acceptor site and the exon 2 translation initiation codon found at that position in other species. An in-frame ATG in strong Kozak consensus context was observed in the normal dog sequence 12 codons 5' of the usual mammalian start site, suggesting that dogs have lost the noncoding exon 1 demonstrated in human and mouse. A survey of TPO sequences in other carnivore species indicates that the poly-G tract necessitating an alternative translation initiation site is a canid-specific feature.

Changes in growth hormone (GH), GH receptor, and GH signal transduction in hippocampus of congenital hypothyroid rats.

Recent studies have shown that, like thyroid hormone (TH), growth hormone (GH) plays a critical role in development of the brain. However, it is still unclear whether the functions of the two hormones are locally orchestrated in the brain or whether TH has a permissive effect on GH in the central nervous system as it does in the periphery. To address this question, the present study investigated the changes in local expression of GH and GH receptor (GHR) and the activity of GH signaling molecules in the hippocampus of congenitally hypothyroid (CHT) rats. As demonstrated by morphometric measurements and the Y-maze test, CHT rats had decreased neurons and weaker Nissl staining in the stratum pyramidal/granule in the hippocampus and a reduced acquisition of safe place recognition memory. Analyses of QPCR and Western blot revealed a substantially decreased hippocampal expression of GH and GHR, accompanied by a corresponding decrease in phosphorylation of JAK2 and STAT5 in the CHT rats. These changes were, at least in part, corrected by systemic supplement of T3. The findings provide the first direct evidence suggesting that the functional autocrine and paracrine regulation of GH in the CNS is orchestrated by TH.

Loss of integrity of thyroid morphology and function in children born to mothers with inadequately treated Graves' disease.

CONTEXT: Central congenital hypothyroidism (CH-C) in neonates born to mothers with inadequately treated Graves' disease usually needs T(4) supplementation. The thyroid and its regulatory system have not yet been extensively studied after T(4) withdrawal, until we observed disintegrated thyroid glands in some patients. OBJECTIVE: The aim was to study the occurrence and pathogenesis of disintegrated thyroid glands in CH-C patients. DESIGN, SETTING, PATIENTS, PARTICIPANTS: Thyroid function was measured and thyroid ultrasound imaging was performed in 13 children with CH-C due to inadequately treated maternal Graves' disease after T(4)-supplementation withdrawal (group Aa). In addition, thyroid ultrasound imaging was performed in six children with CH-C born to inadequately treated mothers with Graves' disease, in whom T(4) supplementation was not withdrawn yet (group Ab) or never initiated (group Ac), in six euthyroid children born to adequately treated mothers with Graves' disease (group B), and in 10 T(4)-supplemented children with CH-C as part of multiple pituitary hormone deficiency (group C). MAIN OUTCOME MEASURES: Thyroid function and aspect (volume, echogenicity, echotexture) were measured. RESULTS: In group A, five children had developed thyroidal hypothyroidism characterized by persistently elevated TSH concentrations and exaggerated TSH responses after TRH stimulation. In the majority of patients in groups A and C, thyroid echogenicity and volume were decreased, and echotexture was inhomogeneous. Thyroid ultrasound imaging was normal in group B children. CONCLUSIONS: Inadequately treated maternal Graves' disease not only may lead to CH-C but also carries an, until now, unrecognized risk of thyroid disintegration in the offspring as well. We speculate that insufficient TSH secretion due to excessive maternal-fetal thyroid hormone transfer inhibits physiological growth and development of the child's thyroid.

Congenital hypothyroidism in one of monozygotic twins: comparison of their long-term psychosomatic development.

Authors present the long-term development of two monozygotic twin sisters. One of them was detected by newborn screening as athyreotic (gemelus A) and healthy gemelus B sister. Therapy in athyreotic girl started at 4 weeks after birth and was monitored in order to maintain serum thyroxine and TSH in normal range. Both sisters spent their chilhood and adolescence together in the same family, school and work together as tailors in the same factory. Their development was very similar. In order to detect subclinical difference of their development, the school achievements were tested using their school certificates. Studies were divided to testing mechanical memory, logical thinking and skills. The evaluation of all classes of school attendance (13 years) reveals subtle differences - deficit of patient at approximately 6-15% level, mainly in studies demanding skills. However, dynamic evaluation after years reveals that the worse results of the patient (gemelus A) occurred during the first years of basic school whereas during adolescence having attended the special school tailor, she attained better results than her healthy sister. It seems that mental deficit in early treated hypothyroid patient is not severe and varies even during the life. Problem of the fetal hypothyroidism is probably more related to the iodine deficiency, which assures necessity of thyroid hormones for athyreotic child from mother's or twin's normally supplemented thyroid glands.

Early effects of iodine deficiency on radial glial cells of the hippocampus of the rat fetus. A model of neurological cretinism.

The most severe brain damage associated with thyroid dysfunction during development is observed in neurological cretins from areas with marked iodine deficiency. The damage is irreversible by birth and related to maternal hypothyroxinemia before mid gestation. However, direct evidence of this etiopathogenic mechanism is lacking. Rats were fed diets with a very low iodine content (LID), or LID supplemented with KI. Other rats were fed the breeding diet with a normal iodine content plus a goitrogen, methimazole (MMI). The concentrations of -thyroxine (T4) and 3,5,3'triiodo--thyronine (T3) were determined in the brain of 21-d-old fetuses. The proportion of radial glial cell fibers expressing nestin and glial fibrillary acidic protein was determined in the CA1 region of the hippocampus. T4 and T3 were decreased in the brain of the LID and MMI fetuses, as compared to their respective controls. The number of immature glial cell fibers, expressing nestin, was not affected, but the proportion of mature glial cell fibers, expressing glial fibrillary acidic protein, was significantly decreased by both LID and MMI treatment of the dams. These results show impaired maturation of cells involved in neuronal migration in the hippocampus, a region known to be affected in cretinism, at a stage of development equivalent to mid gestation in humans. The impairment is related to fetal cerebral thyroid hormone deficiency during a period of development when maternal thyroxinemia is believed to play an important role.

[Stereological studies on the brain development of fetuses in cretinism endemic region after supplement of iodized salt for 10 years].

Epidemiologic reports indicated that in the cretinism endemic regions the incidence of cretinism decreased obviously after supplement of iodized salt but there still existed many cretinoid cases accompanied with mild impairment of intelligence and retardation of somatic development. This suggests that some factors other than iodine deficiency might also play an important role in the pathogenesis of cretinism. 21 brains of therapeutically aborted fetuses from cretinism endemic region after a supplement of iodized salt for ten years were studied under both light and electron microscopes. Serum T3, T4 and TSH of the fetuses and their mothers were coincidentally assayed. The brain development of fetuses from the endemic region was noticed to be still retarded as compared with those from the non-endemic region, despite that the serum hormones of the fetuses and their mothers in the endemic region showed no more significant difference from those in the non-endemic region. The retardation of the brain development could be evidenced by the increase of cellular density, decrease of the average volume of neurocytes, increase of the volume ratio between nucleus and cytoplasma per neuron, as well as decrease in number and average surface area of the mitochondria, and all of these were obtained in the cerebral cortex, hippocampus and the layer of Purkinje's cells of the cerebellum.