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Genetic defects in the TSH receptor (TSHR) can cause poor thyroid differentiation (thyroid dysgenesis) and/or thyroid malfunction (thyroid dyshormonogenesis). The phenotype spectrum is wide: from severe congenital hypothyroidism to mild hyperthyrotropinemia. Over 250 TSHR variants have been published, many uncharacterized in vitro. We aimed to genetically characterize patients with thyroid dyshormonogenesis with TSHR defects and to study in vitro the effect of the genetic variants to establish the genotype–phenotype relationship. Pediatric patients with thyroid dyshormonogenesis (160 patients, Catalan CH neonatal screening program, confirmation TSH range: 18.4–100 mIU/L), were analyzed by a high-throughput gene panel. In vitro studies measuring the TSH-dependent cAMP–response–element activation were performed. Five patients with mild or severe thyroid dyshormonogenesis presented six TSHR variants, two unpublished. Each variant showed a different in vitro functional profile that was totally or partially deleterious. Depending on the genotype, some of the variants showed partial deficiency in both genotypes, whereas others presented a different effect. In conclusion, the percentage of patients with thyroid dyshormonogenesis and candidate variants in TSHR is 3.13%. Our in vitro studies contributed to the confirmation of the pathogenicity of the variants and highlighted the importance of studying the effect of the patient's genotype for a correct diagnostic confirmation. [ABSTRACT FROM AUTHOR]

Thyroid dyshormonogenesis (THD) is a heterogeneous group of genetic diseases caused by the total or partial defect in the synthesis or secretion of thyroid hormones. Genetic variants in DUOX2 can cause partial to total iodination organification defects and clinical heterogeneity, from transient to permanent congenital hypothyroidism. The aim of this study was to undertake a molecular characterization and genotype–phenotype correlation in patients with THD and candidate variants in DUOX2. A total of 31 (19.38%) patients from the Catalan Neonatal Screening Program presented with variants in DUOX2 that could explain their phenotype. Fifteen (48.39%) patients were compound heterozygous, 10 (32.26%) heterozygous, and 4 (12.90%) homozygous. In addition, 8 (26.67%) of these patients presented variants in other genes. A total of 35 variants were described, 10 (28.57%) of these variants have not been previously reported in literature. The most frequent variant in our cohort was c.2895_2898del/p.(Phe966SerfsTer29), classified as pathogenic according to reported functional studies. The final diagnosis of this cohort was permanent THD in 21 patients and transient THD in 10, according to reevaluation and/or need for treatment with levothyroxine. A clear genotype–phenotype correlation could not be identified; therefore, functional studies are necessary to confirm the pathogenicity of the variants. [ABSTRACT FROM AUTHOR]

Introduction: Defects in any thyroid hormone synthesis steps cause thyroid dyshormonogenesis (THD). THD due to thyroglobulin (TG) gene variants is a cause of congenital hypothyroidism (CH) with a wide clinical spectrum, ranging from mild to severe permanent hypothyroidism. We present high-throughput sequencing results of patients with TG variants. Methods: A CH high-throughput sequencing-panel of the main genes involved in the regulation of thyroid hormonogenesis was performed to identify those TG variants that may be related to patient THD phenotype. Results: We identified 21 TG gene variants in 19 patients (11.8%) which could explain their phenotype. Ten of those (47.6%) were not previously described. CH was biochemically severe in these 19 patients. Eight of them were reevaluated after one month of discontinuing LT4 treatment and all had severe permanent hypothyroidism. We also identified another 16 patients who presented heterozygous TG variants, of whom, at reevaluation, five had mild permanent and only one had severe permanent hypothyroidisms. Discussions: In this study, 10 novel and 11 previously reported variants in the TG gene have been identified that could explain the phenotype of 19 patients from non-consanguineous families from a large THD cohort. Although not all these TG gene variants can explain all the patients' THD phenotypes, some of them had severe or mild permanent hypothyroidism at reevaluation. [ABSTRACT FROM AUTHOR]

Prolyl endopeptidase-like (PREPL) deficiency (MIM#616224) is a rare congenital disorder characterised by neonatal hypotonia and feeding difficulties, growth hormone (GH) deficiency and hypergonadotropic hypogonadism. This syndrome is an autosomal recessive disease resulting from mutations in the PREPL gene (MIM#609557). Herein we report a 7-year-old female patient with biallelic mutations in PREPL (c.1528C>T in one allele and whole gene deletion in the other) with early growth impairment in infancy. GH deficiency was confirmed at 20 months of life. Recombinant GH treatment was introduced with a good response. Her clinical features were similar to those of previously reported cases. The description of new patients with PREPL deficiency syndrome is essential to better delineate the phenotypic and genotypic spectrum of the disease. [ABSTRACT FROM AUTHOR]

Long-term treatment with glucocorticoids in patients with congenital adrenal hyperplasia (CAH) does not appear to affect bone mineral density (BMD), although final adult height is decreased. BMD values were obtained on 33 patients with CAH that had been treated since infancy with hydrocortisone. When compared to values from 471 healthy people, BMD was not significantly reduced. Four of the patients had strikingly low BMD values, although their treatment had been similar to the others. This suggests individual factors may affect BMD more than steroidal treatment. Almost all CAH patients failed to achieve optimal adult height., Objective. To evaluate bone mineral density (BMD) in prepubertal and in adolescent and young adult patients with the salt-wasting form of congenital adrenal hyperplasia (CAH). Design. A relationship between bone mineral content and risk for osteoporotic fractures has been observed in adulthood. Infancy, childhood, and adolescence are critical periods for skeletal mineralization; thus, chronic diseases may impair bone mass peaking, particularly if children and adolescents are overexposed to glucocorticoids, as may occur in patients with CAH. Lumbar L2-L4 BMD values were measured by dual x-ray absorptiometry and compared with those of 471 age- and sex-matched controls. Patients. Thirty-three patients with the salt-wasting form of CAH were studied. Sixteen (10 girls and 6 boys; age range, 1.5 to 8.3 years) were prepubertal and 17 (13 women and 4 men; age range, 17.1 to 28.2 years) were adolescent and young adults who had reached final height and had presented normal pubertal development and normal gonadal function thereafter. The average doses of hydrocortisone (Mg/[m.sub.2] body surface/day) received from diagnosis in the neonatal period to BMD evaluation were 21.2 [+ or -] 2.2 and 22.3[+ or -] 2.6, respectively. Results. Mean BMD Z score values were 0.16 [+ or -]1.01 in prepubertal patients and 0.06[+ or -]1.02 in adolescent and young adult patients with no statistically significant differences with age- and sex-matched controls. Mean height Z score values were -0.03 [+ or -]1.13 in prepubertal patients and -1.13[+ or -]0.62 in adolescent and young adult patients with significant differences between the latter and their respective age- and sex-matched controls. Conclusion. Long-term glucocorticoid therapy does not impair bone mass peaking in CAH patients with normal gonadal function, even though their adult height values are low. Pediatrics 1997;100:671-674; salt-wasting form of congenital adrenal hyperplasia, skeletal mineralization, bone mass peaking, bone mineral density, gonadal function, adult height., Adequate skeletal growth and mineralization are important therapeutic goals in classic congenital adrenal hyperplasia (CAH). Different factors such as age at diagnosis, clinical variants, and the degree of hormone control [...]