Thyroid volume is the key predictor of hyperthyroidism remission after radioactive iodine therapy in pediatric patients.

Graves' disease (GD) is the leading cause of hyperthyroidism in pediatric patients. Radioactive iodine therapy (RAIT) is widely used to treat GD. However, it is still unclear exactly what determines the efficacy of RAIT in childhood and adolescence. The objective of our study was to reveal the most significant predictors of the efficacy of RAIT in pediatric GD patients. A single-center prospective observational exploratory study enrolled 144 pediatric patients (124 females and 20 males) between 8 and 18 years of age who underwent dosimetry-guided RAIT for GD for the first time. The estimated parameters included sex, age, thyroid volume, thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone receptor antibodies (TRABs) at baseline and 12 months after RAIT, 10- to 20-min 99mTc thyroid uptake (%), maximum thyroid 131I uptake (%), specific 131I uptake (MBq/g), and therapeutic activity of 131I (MBq), which was limited to 1100 MBq. The Fisher's exact test, Mann-Whitney U-test, Wilcoxon signed-rank test, ROC analysis, and the Youden index were used for statistical analysis. Twelve months after RAIT, 119 patients (83%) successfully achieved remission, 6 patients (4%) had euthyroidism, and hyperthyroidism persisted in 19 patients (13%). Thyroid volume decreased from 17.6 [14.6; 24.1] to 9.3 [7.6; 13.3] mL 12 months after the treatment (p < 0.001). The main predictor that showed a statistically significant difference between the groups of patients who achieved and did not achieve remission of GD hyperthyroidism after RAIT was the initial thyroid volume. Using the Youden index, the optimal cut-off point for the initial thyroid volume at 45.4 mL was determined.     Conclusion: The dosimetry-guided RAIT in pediatric GD patients was 83% effective at 12 months after the treatment, and the initial thyroid volume of less than 45.4 mL was the most important predictor of RAIT success. Other predictors identified in our work included FT4 levels, TRABs levels, 99mTc-pertechnetate uptake, and specific 131I uptake. What is Known: •Radioiodine therapy is a common, effective, and safe treatment for pediatric patients with Graves' disease. What is New: •The initial thyroid volume in pediatric GD patients is an important predictor of achieving hypothyroidism following radioiodine therapy. If the thyroid volume is less than 45.4 ml, radioiodine therapy limited to 1100 MBq will be effective definitive treatment.

High frequency of mutations in 'dyshormonogenesis genes' in severe congenital hypothyroidism.

OBJECTIVE: Results of the screening of disease causative mutations in congenital hypothyroidism (CH) vary significantly, depending on the sequence strategy, patients' inclusion criteria and bioinformatics. The objective was to study the molecular basis of severe congenital hypothyroidism, using the next generation sequencing (NGS) and the recent guidelines for assessment of sequence variants. DESIGN: 243 patients with CH (TSH levels at neonatal screening or retesting greater than 90 mU/l) and 56 control subjects were included in the study. METHODS: A custom NGS panel targeting 12 CH causative genes was used for sequencing. The sequence variants were rated according to American College of Medical Genetics and Genomics (ACMG) guidelines. RESULTS: In total, 48 pathogenic, 7 likely pathogenic and 57 variants of uncertain significance were identified in 92/243 patients (37.9%), while 4 variants of uncertain significance were found in 4/56 control subjects (7.1%). 13.1% (12/92) of the cases showed variants in 'thyroid dysgenesis' (TD) genes: TSHR, n = 6; NKX2-1, n = 2; NKX2-5, n = 1; PAX8, n = 3. The variants in 'dyshormonogenesis' (DH) genes were found in 84.8% (78/92) of cases: TPO, n = 30; DUOX2, n = 24; TG, n = 8; SLC5A5, n = 3; SLC26A4, n = 6; IYD, n = 1. 8 patients showed oligonenic variants. The majority of variants identified in DH genes were monoallelic. CONCLUSIONS: In contrast to earlier studies demonstrating the predominance of TD in severe CH, the majority of variants identified in our study were in DH genes. A large proportion of monoallelic variants detected among DH genes suggests that non-mendelian mechanisms may play a role in the development of CH.

Mutations and pituitary morphology in a series of 82 patients with PROP1 gene defects.

BACKGROUND/AIMS: Defects of the PROP1 gene are the most prevalent genetic cause of combined pituitary hormone deficiency. Previous observations in affected patients have shown pituitary size ranging from hypoplasia to overt pituitary mass and evolution of size over the lifespan. METHODS: We evaluated pituitary size and morphology in PROP1-mutation carriers who originated from Central and Eastern Europe. We analyzed 112 pituitary magnetic resonance imaging (MRI) scans from 82 patients (42 males) aged 2.5-72.7 (median 16.6) years from 60 kindreds. RESULTS: Among the 120 independent PROP1 alleles, the most prevalent mutations were delGA301/302 (99 alleles) and delA150 (13 alleles). Median pituitary height at first MRI was 4.7 mm (range 1.0-20.7) and median volume was 127.6 mm(3) (range 7.5-3,087.0). Pituitary size did not differ between sexes and did not correlate with hormonal phenotype, but significantly decreased with increasing age. However, evaluation of individual values suggested a biphasic mode with increasing volume during childhood, peak in adolescence, and subsequent regression in adulthood. CONCLUSION: Although pituitary size was increased in a number of PROP1-deficient patients, none of them suffered permanent damage from pituitary mass; therefore, any proposed surgery should be postponed as long as possible and ultimately may not be necessary due to the self-limiting nature of the pituitary enlargement.

A novel C-terminal growth hormone receptor (GHR) mutation results in impaired GHR-STAT5 but normal STAT-3 signaling.

GH insensitivity (GHI) is an autosomal recessive disorder caused by defects in the GH receptor (GHR). In a 17-yr-old female with severe short stature and biochemical features of GHI, sequencing of GHR gene revealed a compound heterozygosity for two novel mutations: C83X and a G deletion at position 1776 (1776del). 1776del is predicted to result in GHR truncation to 581 amino acids with a nonsense sequence of residues 560-581. To clarify the effect of 1776del on GHR function, wild-type GHR, GHR-1776del, and two additional GHR mutants, GHR-L561X (stop codon at site of the 1776del) and GHR-I582X (translation termination in GHR-1776del) were transiently expressed in CHO cells. After incubation with recombinant human GH, GHR-1776del showed lower signal transducer and activator of transcription 5 (STAT5)-mediated transcriptional activation ( approximately 50%, P < 0.05), as well as STAT5 Tyr694 phosphorylation (P < 0.05) compared with wild-type GHR, whereas GHR-L561X and GHR-I582X showed normal STAT5 phosphorylation and transcriptional activity. In contrast, all vectors produced similar effects on STAT3-mediated transcriptional activation. In conclusion, this novel GHR-1776del mutation in a classical GHI patient illustrates an important mechanism of impaired GHR-STAT5 but intact GHR-STAT3 signaling. This effect might result from interference of C-terminal nonsense sequence in mutated GHR with STAT5 docking to upstream tyrosine residues.