Search

Objectives: Sex steroids, administered as a priming before GH stimulation tests (GHST) to differentiate between growth hormone deficiency (GHD) and constitutional delay of growth and puberty (CDGP) or as growth-promoting therapy using low-dose sex steroids (LDSS) in CDGP, are much debated. We aimed to compare auxological outcomes of CDGP or GHD children undergoing primed or unprimed GHST and to evaluate LDSS treatment in CDGP. Design: Retrospective study among three paediatric University Hospitals in Italy and UK. Methods: 184 children (72 females) aged 12.4±2.08years underwent primed (/P+) or unprimed (/P−) GHST and were followed up until final height (FH). CDGP patients were untreated (CDG P−) or received LDSS (CDGP+). The cohort included 34 CDG P−/P+, 12 CDGP+/P+, 51 GHD/P+, 29 CDG P−/P−, 2 CDGP+/P− and 56 GHD/P−. FH standard deviation score (SDS), Δ SDS FH-target height (TH) and degree of success (−1≤Δ SDS FH-SDS TH ≤ +1) were outcomes of interest. Results: GHD/P+ had better FH-SDS (−0.87 vs −1.49; P=.023) and ΔSDS FH-TH (−0.35 vs −0.77; P=.002) than CDGP−/P+. Overall, GHD/P+ showed the highest degree of success (90%, P=.006). Regardless of priming, both rhGH and LDSS improved degree of success compared to no treatment (89% and 86% vs 63%, P=.0009). GHD/P+ showed a trend towards a higher proportion of permanent GHD compared to GHD/P- (30.43% vs 15.09%; P=.067). Conclusion: In peripubertal children, priming before GHST improves diagnostic accuracy of GHST for idiopathic GHD. LDSS treatment improves auxological outcomes in CDGP.

Background Long-term consequences of mild subclinical hypothyroidism (SH) in children are still unclear, and the need for levothyroxine (L-T4) supplementation remains controversial. We designed a 2-year, case-control, prospective study of a cohort of children with SH to evaluate the effects of L-T4 therapy on neurocognitive outcome. Methods Thirty-four children, age 9.1 ± 2.6 years, with long-lasting, idiopathic, and mild SH, and 34 healthy matched controls, were enrolled. Twenty SH children underwent a 2-year L-T4 treatment (group A), whereas 14 refused treatment and were reevaluated after a 2-year-follow-up (group B). IQ and specific cognitive domains were evaluated in all children at study entry and after 2 years of therapy (group A) or observation (group B) in SH individuals. Results In SH children baseline IQ scores were normal and comparable to controls (full-scale IQ [FSIQ] 100.4 ± 11.3 vs 101.8 ± 14.2, verbal IQ [VIQ] 99.7 ± 13.7 vs 98.3 ± 14.9 and performance IQ [PIQ] 101.2 ± 10.4 vs 105 ± 10.4). In group A, L-T4 treatment was associated with normalization of thyrotropin (6.3 ± 1.0 mIU/L at baseline vs 2.8 ± 1.4 mIU/L at 2 years, P Conclusions Our data suggest neurocognitive function in children is not impaired by persistent, mild, untreated SH and is not significantly modified by 2-year L-T4 supplementation.

Increasing evidence indicate that adults with Congenital Adrenal Hyperplasia (CAH) may have a cluster of cardiovascular (CV) risk factors. In addition, ongoing research have highlighted that children and adolescents with CAH are also prone to develop unfavorable metabolic changes, such as obesity, hypertension, insulin insensitivity, and increased intima-media thickness, which place them at a higher risk to develop CV disease in adulthood. Moreover, CAH adolescents may exhibit subclinical left ventricular diastolic dysfunction and impaired exercise performance, with possible negative consequences on their quality of life. The therapeutic management of patients with CAH still remains a challenge and current treatment regimens do not always allow optimal biochemical control. Indeed, overexposure to glucocorticoids and mineralcorticoids as well as to androgen excess may contribute to the development of unfavorable metabolic and CV abnormalities. Long-term prospective studies on large cohorts of patients will help to clarify the pathophysiology of metabolic alterations associated to CAH. In the meanwhile, further efforts should be made in order to optimize treatment and identify new therapeutic approaches to prevent metabolic derangement and improve long-term health outcomes of CAH patients.

BACKGROUND: Congenital hypothyroidism is a frequent disease occurring with an incidence of about 1/1500 newborns/year. In about 75% of the cases, CH is caused by alterations in thyroid morphogenesis, defined "thyroid dysgenesis" (TD). TD is generally a sporadic disease but in about 5% of the cases a genetic origin has been demonstrated. Previous studies indicate that Dnajc17 as a candidate modifier gene for hypothyroidism, since it is expressed in the thyroid bud, interacts with NKX2.1 and PAX8 and it has been associated to the hypothyroid phenotype in mice carrying a single Nkx2.1 and Pax8 genes (double heterozygous knock-out). PURPOSE: The work evaluates the possible involvement of DNAJC17 in the pathogenesis of TD. METHODS: High-resolution DNA melting analysis (HRM) and direct sequencing have been used to screen for mutations in the DNAJC17 coding sequence in 89 patients with TD. RESULTS: Two mutations have been identified in the coding sequence of DNAJC17 gene, one in exon 5 (c.350A>C; rs79709714) and one in exon 9 (c.610G>C; rs117485355). The last one is a rare variant, while the rs79709714 is a polymorphism. Both are present in databases and the frequency of the alleles is not different between TD patients and controls. CONCLUSIONS: DNAJC17 mutations are not frequently present in patients with TD.

BACKGROUND: Autoimmune polyendocrine syndrome type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy, is a rare autosomal recessive disease due to pathogenic variants in the AIRE gene. Classic features of the syndrome are mucocutaneous candidiasis, chronic idiopathic hypoparathyroidism and Addison disease. However, other endocrine and non-endocrine components, may occur with a different prevalence. In addition to ectodermal features, which are quite common features of the disease, APS 1 patients may experience other types of skin alterations, such as vasculitic skin rash. An early diagnosis of APS 1 can be very challenging, due to the high clinical heterogeneity, and a considerable delay may occur between the appearance of symptoms and the diagnosis. CASE PRESENTATION: We report on a girl affected by APS 1 who presented with cutaneous vasculitis when she was seven-months old, some years before the onset of the common components of the disease. CONCLUSION: Clinical picture of APS 1 may be characterized by isolated rare or atypical autoimmune or immune-mediated manifestations, even years before the onset of the classic components of the disease. Among these uncommon features, skin rashes of variable form and duration may occur, most of them being associated with histopathological features of vasculitis. Our case suggests that cutaneous vasculitis may represent a first sign of APS 1. The clinical significance of cutaneous vasculitis in the context of APS 1 is still debated. It may represent a rare, unusual, early component of the disease or a clinical manifestation secondarily related to the typical APS 1 components (i.e. autoimmune thyroid disease), which are frequently associated with rheumatologic-like signs and symptoms. Alternatively, it may be the expression of an independent disease co-occuring with APS 1. In conclusion, our case suggests that children presenting with unexplained vasculitic skin rash should be followed-up in order to early identify APS 1.

ObjectiveThe 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 methodsClinical 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.ResultsAt 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.ConclusionsPersistent 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.

Noonan-like syndrome with loose anagen hair (NS/LAH; OMIM #607721) has been recently related to the invariant c.4A > G missense change in SHOC2. It is characterized by features reminiscent of Noonan syndrome. Ectodermal involvement, short stature associated to growth hormone (GH) deficiency (GHD), and cognitive deficits are common features. We compare in two patients with molecularly confirmed NS/LAH diagnosis, the clinical phenotype and pathogenetic mechanism underlying short stature. In particular, while both the patients exhibited a severe short stature, GH/IGFI axis functional evaluation revealed a different pathogenetic alteration, suggesting in one patient an upstream alteration (typical GHD) and in the other one a peripheral GH insensitivity. Since only a few cases of NS/LAH associated to SHOC2 mutations have been so far described, the complex phenotype of the syndrome and the exact mechanism impairing GH/IGFI axis still remain to be elucidated and studies on larger cohort of subjects are needed to better delineate this syndrome.

Introduction Turner Syndrome (TS) is caused by monosomy or structural abnormalities of the X chromosome, with a prevalence of about 1/2000 females live birth. Most important clinical features of TS are short stature and gonadal failure. Approximately one third of girls with TS may undergo spontaneous puberty. Here we report on the case of a girl with a rare 45X0/47XXX mosaic TS exhibiting a precocious puberty. Case report The patient was diagnosed with TS at the age of 4 years, upon a diagnostic work-up for dysmorphic features. Chromosome analysis revealed a mosaic karyotype (45X0/47XXX). She presented with normal height and normal growth velocity so that Growth Hormone (GH) therapy was not started. She was referred to our Department at the age of 7 years and 10 months, because of vaginal bleeding. A physical examination revealed a Tanner stage III for breast and Tanner stage III for pubic hair development. Height and weight were within the normal range for age. Psychological evaluation showed moderate global developmental delay, together with emotional and social immaturity and reading difficulties. The growth rate was accelerated. Her bone age was 10 years. Pelvic ultrasound demonstrated increased size for age of both the uterus and the ovaries, with bilateral ovarian follicles. GnRH stimulation test revealed pubertal response of gonadotropins (peak LH 22.5 mIU/ml). MRI of the brain was normal. These clinical, radiologic and laboratory findings were consistent with a diagnosis of idiopathic central precocious puberty; therefore, GnRH analog therapy was started, in order to slow pubertal progression and to preserve adult stature. Furthermore, GH treatment was added to further improve adult height. Conclusion Our case highlights the possibility of precocious puberty as an atypical clinical feature of TS. Thus, precocious puberty may occur in TS girls when a dosage compensation by the cell line with more than two X chromosomes allows normal ovarian function. GnRH analog therapy in addition to GH treatment should be recommended in TS girls with precocious puberty in order to slow pubertal progression and to preserve adult stature.