Context: Premature ovarian failure (POF) is a cause of female infertility characterized by primary (PA) or secondary amenorrhea (SA) and elevated gonadotropins. The pathogenesis is unknown in most cases. We recently reported two sisters with PA carrying a heterozygous mutation of BMP15 gene (locus Xp11.2), but the prevalence of BMP15 variations in the POF population is unknown. Objective: The objective of the study was to verify the involvement of BMP15 variations in a large POF population. Design and Subjects: Genetic screening of 166 unrelated patients with idiopathic POF (25 PA, 141 SA) and controls (group A: 95 women with menopause beyond 50 yr of age; group B: 86 women and 30 men from the general population) of Caucasian origin. Results: Investigation revealed four heterozygous variations affecting the proregion of BMP15. The previously reported p.Y235C mutation occurred in one and three novel variants in eight patients: two missense alterations (p.R68W in one case, p.A180T in five) and one insertion (p.262insLeu) in two cases. The p.262insLeu was found in five controls of group A, thus diminishing its potential biological impact, whereas the other three variants were not present in any of the controls. All new mutations were found in SA cases. Conclusion: We describe the significant association of heterozygous BMP15 gene variants with the POF phenotype in humans (seven of 166 patients: 4.2%; P < 0.003 vs. controls). These findings are consistent with the critical role played by BMP15 in human folliculogenesis.

Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome‐linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations.

Objective To investigate the association between juvenile autoimmune thyroiditis (JAT) and thyroid cancer in pediatric patients. Design We conducted a retrospective study among children and adolescents affected by JAT. Settings Data from 6 Italian pediatric endocrinology centers were collected. Participants Three hundred sixty-five children and adolescents affected by JAT diagnosed at 3.6 to 17.0 years of age. Interventions All patients underwent clinical examination and thyroid function test every 6 to 12 months and thyroid echography every 12 to 24 months. Fine-needle aspiration biopsy was performed in 39 patients with nodule diameter of 1 cm or larger, as well as in 4 patients with nodule diameter of less than 1 cm and echographic findings suspicious for neoplasm. Twenty-three patients underwent surgery. Main Outcome Measures Thyroid function, echographic pattern, nodule diameter, the presence of lymphadenopathy, and cytologic and histologic diagnoses were considered. Results Thyroid nodules were found in 115 patients; findings in 11 of these were consistent with papillary carcinoma, with 5 exhibiting lymph node metastasis. The prevalence of male sex among patients with cancer was greater than that among patients with JAT (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.44-6.20). The growth of nodules during levothyroxine sodium therapy (OR, 15.60; 95% CI, 1.87-181.90) and the finding of lymphadenopathy (OR, 5.44; 95% CI, 1.05-30.50) were statistically significantly associated with the presence of cancer, while uninodularity and hypoechogenicity were not. Conclusions The observed prevalences of thyroid nodules and thyroid cancer in our JAT case series were 31.5% and 3.0%, respectively. Papillary carcinoma was the only histotype detected. The finding of lymphadenopathy, a lack of response to levothyroxine therapy, and nodule hypoechogenicity suggested malignancy. Fine-needle aspiration biopsy was reliable in selecting patients for referral to surgery.

Objective: To prospectively evaluate the course of subclinical hypothyroidism (SH) in children and adolescents with no underlying diseases and no risk factors, which might interfere with the progression of SH.Design: Clinical status, thyroid function, and autoimmunity were prospectively evaluated at entry and after 6, 12, and 24 months in 92 young patients (mean age 8.1±3.0 years) with idiopathic SH.Results: During the study, mean TSH levels showed a trend toward a progressive decrease while FT₄ levels remained unchanged. Overall, 38 patients normalized their TSH (group A): 16 patients between 6 and 12 months, and 22 patients between 12 and 24 months. Among the remaining 54 patients, the majority maintained TSH within the baseline values (group B), whereas 11 exhibited a further increase in TSH above 10 mU/l (group C). Baseline TSH and FT₄ levels were similar in the patients who normalized TSH, compared with those with persistent hyperthyrotropinemia. Even in the patients of group C, both TSH and FT₄ at entry were not different with respect to those of groups A and B. No patients showed any symptoms of hypothyroidism during follow-up and no changes in both height and body mass index were observed throughout the observation period.Conclusions: (a) The natural course of TSH values in a pediatric population with idiopathic SH is characterized by a progressive decrease over time; (b) the majority of patients (88%) normalized or maintained unchanged their TSH; and (c) TSH changes were not associated with either FT₄ values or clinical status or auxological parameters.

The aim of this retrospective study was to analyze the factors which affected the auxological response to GnRH agonist treatment and the final height (FH) outcome in 71 girls with idiopathic and truly precocious (onset before 8 years) central puberty (CTPP) who had been treated with the same therapy protocol (Decapeptyl Depot, 60 microg/kg i.m. every 28 days) for at least 2 years (since 7.0+/-1. 3 (S.D.) years of age) and followed until puberty was completed and FH was reached. During the entire treatment period we observed: (a) a decrease of height standard deviation scores (SDS) (from 1.5+/-1.7 to 0.9+/-1.3 SDS, P<0.01); (b) a striking deceleration of bone age (BA), revealed by the subnormal DeltaBA:Deltachronological age (CA) ratio (0.2+/-0.1); (c) an increase of predicted adult height (from 155.6+/-7.0 to 160.7+/-6.7 cm, P<0.0005). Treatment interruption was followed by an important catch-down growth, with an FH (158.4+/-5.8 cm) lower (P<0.025) than that predicted at the end of therapy. However, FH fell within the population norm and the target range in respectively 87.3 and 90% of the patients. The tallest FH was recorded in the patients who started therapy at less than 6 years of age and in those who discontinued treatment at a BA of 12.0--12.5 years. At stepwise regression analysis, FH in the whole study population was positively affected by the following independent factors: (a) height at the end of therapy (F=45.45, P<0.0001); (b) pretreatment height (F=13.91, P<0.0005); (c) treatment duration (F=8. 51, P<0.005); (d) target height (TH) (F=7.70, P<0.01). We conclude that: (i) most girls with idiopathic CTPP treated by GnRH agonists may achieve an adult height within the population norm and/or their target range; (ii) the height gain from therapy onset until FH attainment, however, is generally rather limited (on average 2.9 cm) and only few patients are able to reach their target percentile; (iii) the most favorable height prognosis with respect to TH is generally observed in the subjects with the tallest height at the end of treatment and the lowest BA2:CA2 ratio, due to the important deterioration of height prognosis which frequently follows therapy interruption; (iv) FH is also significantly conditioned by both TH and treatment duration; (v) in order to strengthen the weak therapeutic effect of GnRH agonists in CTPP this treatment should be started as early as possible and discontinued at a BA of 12.0--12.5 years.

Objective The treatment of children with subclinical hypothyroidism (SH) is controversial for TSH values between 4.5 and 10 mU/l. The aim of this cross-sectional, controlled study was to evaluate growth and intellectual outcome in children with persistent SH who have never been treated with levothyroxine. Design and methods Clinical and auxological parameters, thyroid function, and intellectual outcome were evaluated in 36 children with persistent SH at the age of 9.7±0.6 (range 4–18.0) years. Children had been followed longitudinally for 3.3±0.3 (range 2.0–9.3) years, from first diagnosis of SH until enrollment in the study. Thirty-six age- and sex-matched children were enrolled in the study as controls. Results At study entry, height (−0.8±0.2 SDS), bone age/chronological age (BA/CA ratio 0.92±0.6), and body mass index (BMI −0.1±0.2 SDS) in SH children were normal. Despite long-term duration of SH, none of these parameters showed a worsening with respect to height (−0.7±0.2 SDS), BA/CA (0.97±0.03), and BMI (−0.1±0.2) at the time of first SH detection. None of the children showed overt signs or symptoms of hypothyroidism during the follow-up. Verbal (99.1±2.2), performance (100.4±1.9), and full-scale (99.7±1.9) intelligence quotient (IQ) scores in SH children were normal and comparable to those of controls. No relationship was detected between IQ scores and the degree or duration of SH. Conclusions Persistent SH in children is not associated with alterations in growth, bone maturation, BMI, and cognitive function or other complaints that could be ascribed to SH even after several years without therapeutic intervention.