Diagnostic evaluation in steroid-induced myopathy: case report suggesting clinical utility of quantitative muscle ultrasonography.

PURPOSE: We present a patient with adrenal Cushing's syndrome causing steroid myopathy. The purpose of the case report is to illustrate the clinical usefulness of quantitative muscle ultrasonography for the assessment of glucocorticoid-induced changes in muscle mass (MM) and structure. METHODS: Assessments of physical performance, muscle strength, MM (i.e., total body skeletal MM, appendicular skeletal MM, and thickness of lower limb muscles), and muscle structure (i.e., echo intensity of lower limb muscles) were performed in the patient both in the active phase of the disease (preoperatively) and 6 months after surgical intervention (postoperatively). RESULTS: Muscle strength, physical performance, and MM were low both preoperatively and postoperatively. We also found preoperatively an increased echo intensity that normalized postoperatively. CONCLUSIONS: Clinical implications of these findings are double-fold. First, although the muscle structure can recover quickly in steroid myopathy patients, the recovery of MM may take months to years. Second, we show that muscle echo intensity can be useful to track the progression of steroid myopathy overtime and may help to indicate early response to therapeutic interventions. Further prospective studies are needed to confirm the value of muscle echo intensity in patients with endogenous or exogenous Cushing's syndrome presenting with steroid myopathy.

Preexisting autoantibodies to type I IFNs underlie critical COVID-19 pneumonia in patients with APS-1.

Patients with biallelic loss-of-function variants of AIRE suffer from autoimmune polyendocrine syndrome type-1 (APS-1) and produce a broad range of autoantibodies (auto-Abs), including circulating auto-Abs neutralizing most type I interferons (IFNs). These auto-Abs were recently reported to account for at least 10% of cases of life-threatening COVID-19 pneumonia in the general population. We report 22 APS-1 patients from 21 kindreds in seven countries, aged between 8 and 48 yr and infected with SARS-CoV-2 since February 2020. The 21 patients tested had auto-Abs neutralizing IFN-α subtypes and/or IFN-ω; one had anti-IFN-ß and another anti-IFN-ε, but none had anti-IFN-κ. Strikingly, 19 patients (86%) were hospitalized for COVID-19 pneumonia, including 15 (68%) admitted to an intensive care unit, 11 (50%) who required mechanical ventilation, and four (18%) who died. Ambulatory disease in three patients (14%) was possibly accounted for by prior or early specific interventions. Preexisting auto-Abs neutralizing type I IFNs in APS-1 patients confer a very high risk of life-threatening COVID-19 pneumonia at any age.

Orderliness of cortisol, growth hormone, and leptin secretion in short-normal pre-pubertal boys and girls.

BACKGROUND: The approximate entropy (ApEn) of the secretion of one hormone is a measure of its irregularity of secretion, while cross-approximate entropy (cross-ApEn) assesses the interaction between the secretion of two hormones. The aim was to assess the regularity and interplay of the secretory profiles of leptin (Le), cortisol (F), and growth hormone (GH). MATERIAL/METHODS: Spontaneous 24-hour Le, F, and GH secretions were analyzed with ApEn and cross-ApEn in 11 short-normal pre-pubertal children (5 boys and 6 girls). RESULTS: Although the Le, F, and GH levels were not significantly different between the boys and girls, the boys showed more orderly F secretion than the girls, while the latter showed more orderly GH and Le secretions evaluated by ApEn. Moreover, the synchrony between the secretory profiles of Le and the other two hormones as evaluated by cross-ApEn was significantly more regular in the boys. CONCLUSIONS: Differences in the orderliness of secretion of Le, F, and GH were shown between pre-pubertal boys and girls, while increased synchrony was seen between the secretions of Le and GH as well as Le and F in pre-pubertal boys compared with girls. These findings complement the authors' previous research using cross-correlational analyses which demonstrated that the secretory profiles of Le, F, and GH were correlated in time.

Fertility in patients with nonclassical congenital adrenal hyperplasia.

Nonclassical congenital adrenal hyperplasia (NC-CAH) is by far a subtler and milder enzymatic defect to the classical form of the disease. A nuanced understanding of NC-CAH will lead to increased detection of the disorder in those initially misdiagnosed as having polycystic ovary syndrome, will assist in the detection of pregnancies at risk for severe genetic steroid disorders, and will facilitate appropriate ovulation induction and reduction in the hyperandrogenic symptoms which are a cornerstone of the disease. We describe the history of the disease as well as elucidate the pathophysiology, diagnosis, and treatment of the disorder.

Effect of pre-season training phase on anthropometric, hormonal and fitness parameters in young soccer players.

The aims of the study were to investigate 1) the effect of 8 weeks of PSP training on anthropometrics, salivary hormones and fitness parameters in youth soccer players, 2) the correlations between fitness and hormonal parameters, and 3) the impact of the experience of the coach and his methodology of training on these parameters. Weight, height, BMI, pubertal development (PDS), salivary Cortisol (sC), salivary Testosterone (sT), salivary sDHEAS, intermittent tests (VO2max), and countermovement jump test (CMJ) modifications of 35 youth soccer players (age: 14±0 yrs; BMI: 20.8±1.8 k/m2) from two Italian clubs ("Lupa Frascati" -LF-; "Albalonga" -AL) were analysed. A significant (p<0.05) time by club effect was observed in sC (F(1,31) = 9.7, ES = 1.13), sT (F(1,31) = 4.2, ES = 0.74), CMJ (F(1,28) = 26.5, ES = 1.94), and VO2max (F(1,28) = 8.5, ES = 1.10). Statistical differences (p<0.05) in weight (F(1,32) = 25.5, ES = 0.11), sC (F(1,31) = 32.1, ES = 1.43), sT/sC ratio (F(1,31) = 10.1, ES = 0.97), sDHEAS/sC ratio (F(1,31) = 6.3, ES = 0.70), and VO2max (F(1,28) = 64.3, ES = 1.74) were found within time factor. Between clubs, differences (p<0.05) in sC (F(1,32) = 8.5, ES = 1.17), sT (F(1,31) = 4.2, ES = 0.74), CMJ (F(1,28) = 26.5, ES = 1.50), and VO2max (F(1,28) = 8.5, ES = 1.10) were found. CMJ was inversely correlated with sDHEAS (r = -0.38) before PSP, while Δ of CMJ showed significant correlations with Δ of sC (r = 0.43) and ΔVO2max was inversely correlated with ΔBMI (r = -0.54) and ΔsC (r = -0.37) in all subjects. Considering each single club, ΔVO2max showed correlations with ΔBMI (r = -0.45) in AL, while ΔCMJ showed correlations with ΔPDS (r = 0.72) in LF club. Since the PSP is often limited training time to simultaneously develop physical, technical and tactical qualities, an efficient method to distribute the training load is important in youth soccer players to increase the performance and to avoid injuries.

Ghrelin inhibits steroid biosynthesis by cultured granulosa-lutein cells.

CONTEXT: Growing evidence indicates that ghrelin may participate in the regulation of different aspects of reproductive function. The genes encoding for this peptide and its receptor are expressed in the human ovary, but their functional role is still unknown. OBJECTIVE: The aim of our study was to assess whether ghrelin has any effect on steroid synthesis by human granulosa-lutein cells and to identify the receptor isoform through which this potential effect is exerted. DESIGN, PATIENTS, AND METHODS: Thirty-five women with spontaneous ovulatory cycles undergoing in vitro fertilization for infertility due to uni- or bilateral tubal impatency or male factor were studied. Granulosa-lutein cells obtained from follicular fluid were incubated with increasing amounts of human acylated ghrelin (10(-11) to 10(-7) mol/liter) either alone or together with a 1:500 concentration of a specific anti-ghrelin receptor antibody [GH secretagogue receptor 1a (GHS-R1a)]. Culture media were tested for estradiol (E(2)) and progesterone (P(4)). The expression of GHS-R1a and GHS-R1b in human granulosa-lutein cells was also studied by real-time quantitative PCR. RESULTS: E(2) and P(4) concentrations in the culture media were significantly reduced by ghrelin in a dose-dependent fashion. The maximal decrease in E(2) (25%) and P(4) (20%) media concentrations was obtained with the 10(-7) and 10(-8) mol/liter ghrelin concentrations, respectively. The inhibitory effect of all ghrelin concentrations used was antagonized by the specific anti-ghrelin receptor-1a antibody added to the culture media and not by the specific anti-ghrelin receptor-1b antibody. Both 1a and 1b isoforms of the GHS-R were expressed in human granulosa-lutein cells, with the latter exceeding the former's expression (GHS-R1b/GHS-R1a ratio, 143.23 +/- 28.15). CONCLUSIONS: Ghrelin exerts an inhibitory effect on granulosa-lutein cells steroidogenesis by acting through its functional GHS-R1a. This suggests that ghrelin may serve an autocrine-paracrine role in the control of gonadal function and be part of a network of molecular signals responsible for the coordinated control of energy homeostasis and reproduction.

Familial multinodular goiter and Sertoli-Leydig cell tumors associated with a large intragenic in-frame DICER1 deletion.

OBJECTIVE: Familial multinodular goiter (MNG), with or without ovarian Sertoli-Leydig cell tumor (SLCT), has been linked to DICER1 syndrome. We aimed to search for the presence of a germline DICER1 mutation in a large family with a remarkable history of MNG and SLCT, and to further explore the relevance of the identified mutation. DESIGN AND METHODS: Sanger sequencing, Fluidigm Access Array and multiplex ligation-dependent probe amplification (MLPA) techniques were used to screen for DICER1 mutations in germline DNA from 16 family members. Where available, tumor DNA was also studied. mRNA and protein extracted from carriers' lymphocytes were used to characterize the expression of the mutant DICER1. RESULTS: Nine of 16 tested individuals carried a germline, in-frame DICER1 deletion (c.4207-41_5364+1034del), which resulted in the loss of exons 23 and 24 from the cDNA. The mutant transcript does not undergo nonsense-mediated decay and the protein is devoid of specific metal ion-binding amino acids (p.E1705 and p.D1709) in the RNase IIIb domain. In addition, characteristic somatic 'second hit' mutations in this region were found on the other allele in tumors. CONCLUSIONS: Patients with DICER1 syndrome usually present a combination of a typically truncating germline DICER1 mutation and a tumor-specific hotspot missense mutation within the sequence encoding the RNase IIIb domain. The in-frame deletion found in this family suggests that the germline absence of p.E1705 and p.D1709, which are crucial for RNase IIIb activity, may be enough to permit DICER1 syndrome to occur.

Prevalence of obesity in Italian adolescents: does the use of different growth charts make the difference?

BACKGROUND: Since populations are becoming increasingly multi-ethnic, the use of local or international charts is a matter of debate. This study aimed to evaluate how the choice of cut-off thresholds affected prevalence of underweight (UW), overweight (OW), obesity (OB) in 1200 11-12-year Italian adolescents, and how their somatic growth depended on parental origin. METHODS: The height, weight and body mass index were expressed as standard deviation score (SDS) using Italian (ISPED-2006) and UK (UK-1990) charts. The classification of UW/OW/OB was computed with the IOTF international cut-offs, and thresholds were identified as centiles corresponding to BMI values of 18.5/25.0/30.0 kg/m2 at 18-year in ISPED-2006 or UK-1990 references. RESULTS: About 30% participants had non-Italian parents, above all from North-Africa and Romania. Referring to the UK-1990 charts, all groups showed negative mean SDS for height, and positive SDS for weight and BMI. Referring to the ISPED-2006 charts, all mean SDS were negative. Percentage of UW individuals was higher in accordance with ISPED-2006 than with UK-1990 charts, whereas percentages of OW/OB were higher with UK-1990 than ISPED-2006 charts. The results obtained using IOFT cut-offs were similar to UK-1990 cut-offs. These results were due to the different shape of age-dependent cut-off centiles. Independently by the parental origin, the percentages of adolescents classified as OW/OB were closer to the expected values using the ISPED-2006 then the UK-1990 cut-offs. The results suggested the use of the Italian references for adolescents with immigrant parents. CONCLUSION: The use of local charts seems more appropriate at least in Italian adolescents in the age range studied.

Clinical significance of the parental origin of the X chromosome in turner syndrome.

CONTEXT: The phenotype in Turner syndrome (TS) is variable, even in patients with a supposedly nonmosaic karyotype. Previous work suggested that there were X-linked parent-of-origin effects on the phenotype. HYPOTHESIS: The TS phenotype is influenced by the parental origin of the missed X chromosome. DESIGN: This was a multicenter prospective study of TS patients and both their parents, determining parental origin of the X-chromosome, and characterizing the clinical phenotype. PATIENTS AND METHODS: Eighty-three TS patients and their parents were studied. Inclusion criteria were TS with karyotype 45,X or 46Xi(Xq). Four highly polymorphic microsatellite markers on the X-chromosome DMD49, DYSII, DXS1283, and the androgen receptor gene and three Y chromosome markers, SRY, DYZ1, and DYZ3. OUTCOME MEASURES: The study determined the correlation between the parental origin of the X chromosome and the unique phenotypic traits of TS including congenital malformations, anthropometry and growth pattern, skeletal defects, endocrine traits, education, and vocation. RESULTS: Eighty-three percent of 45,X retained their maternal X (X(m)), whereas 64% 46Xi(Xq) retained their paternal X (X(p), P < 0.001). Kidney malformations were exclusively found in X(m) patients (P = 0.030). The X(m) group had lower total and low-density lipoprotein cholesterol (P < 0.003), and higher body mass index sd score (P = 0.030) that was not maintained after GH treatment. Response to GH therapy was comparable. Ocular abnormalities were more common in the paternal X group (P = 0.017), who also had higher academic achievement. CONCLUSIONS: The parental origin of the missing short arm of the X chromosome has an impact on overweight, kidney, eye, and lipids, which suggests a potential effect of an as-yet-undetermined X chromosome gene imprinting.

Prenatal and early postnatal treatment of congenital adrenal hyperplasia.

Congenital adrenal hyperplasia is a group of monogenic autosomal recessive disorders due to an enzyme deficiency in steroid biosynthesis. The most frequent form of congenital adrenal hyperplasia is 21-hydroxylase (21-OH) deficiency, which in its severe form can cause ambiguous genitalia in the female patient. Recent advances in molecular genetic analysis allow for prenatal diagnosis and treatment of at-risk fetuses. The objective of prenatal diagnosis and treatment of 21-OH deficiency is the prevention of prenatal virilization in affected female infants, reducing the risks of sex misassignment and gender confusion, and the need for corrective genital surgery. Prenatal treatment of 21-OH deficiency is effective in reducing genital ambiguity, and short-term outcome studies of children exposed to dexamethasone in utero indicate no significant adverse effects. However, more long-term studies of treated versus untreated pregnancies are warranted to monitor the safety of treatment and enhance our understanding of the effects of prenatal steroid exposure to the human brain. In the first year of life, optimization of medical treatment in salt-wasting patients is achieved by combining the lowest dose of glucocorticoid able to suppress androgen secretion with the normalization of sodium balance by giving appropriate sodium chloride supplementation.

Pituitary Autoimmunity.

Pituitary autoimmunity, considered a synonym of autoimmune hypophysitis, defines a wide spectrum of conditions (neoplastic, functional, and iatrogenic pituitary disorders; and extra-pituitary autoimmune and non-autoimmune diseases), and is characterized by the presence of antipituitary antibodies (APAs) at various titer and prevalence. These conditions have been increasingly recognized not only in adults, but also in children. The autoimmune pathogenesis, histological features of the primary (i.e. lymphocytic, granulomatous, xanthomatous, IgG-4 related lymphoplasmacytic, and necrotizing) forms, and the pathognomonic association of lymphocytic hypophysitis with pregnancy and CTLA-4 antibody therapy, have been clearly demonstrated. Meanwhile, non-invasive differential diagnosis remains extremely challenging since none of the suggested clinical, radiological or laboratory criteria are pathognomonic. In this context, the demonstration of APA is not sufficient, because of the lack of specificity, and associated methodological and theoretical issues (i.e. disease marker vs. pathogen; antigen target(s); and diagnostic/prognostic significance). This chapter aims at providing a comprehensive overview of the pituitary autoimmunity panorama for epidemiological, clinical radiological, and histological aspects, while discussing the main diagnostic limitations and issues associated with disease management.

Final height in girls with central idiopathic precocious puberty treated with gonadotropin-releasing hormone analog and oxandrolone.

CONTEXT: GnRH analogs (GnRHa) are considered the treatment of choice for central precocious puberty (CPP). During GnRHa administration, the suppression of the pituitary-gonadal axis results in decreased rates of linear growth and skeletal maturation and in improved adult height. However, in some patients, the growth deceleration is so marked that the expected improvement in predicted adult height is not achieved. OBJECTIVE: The objective of this study was to assess whether the addition of oxandrolone (Ox) may affect the height outcome of patients with CPP and growth deceleration during GnRHa treatment. DESIGN: This was an open-label, clinical study. SETTING: The study was performed at a pediatric endocrinology referral clinic. PATIENTS: Twenty patients with CPP and marked growth deceleration during GnRHa treatment were studied. INTERVENTIONS: Treatment consisted of GnRHa (Leuprorelina, 3.75 mg im every 28 d) alone (10 patients) or in combination with Ox (0.06 mg/kg.d by mouth) (10 patients). MAIN OUTCOME MEASURE: The main outcome measure was the patients' adult height. RESULTS: The adult height of the patients treated with GnRHa plus Ox was significantly higher than pretreatment predicted adult height (162.6 +/- 2.3 vs. 154.8 +/- 1.7 cm, mean +/- sem; P < 0.05) and target height (162.6 +/- 2.3 vs. 158.0 +/- 1.9; P > 0.05). Patients treated with GnRHa alone reached an adult height similar to the pretreatment predicted adult height (151.9 +/- 1.2 vs. 155.4 +/- 2.1 cm) but significantly lower than target height (151.9 +/- 1.2 vs. 156.6 +/- 1.4 cm; P < 0.005). No side effects were recorded in either group of patients. CONCLUSIONS: Combined GnRHa and Ox therapy is a viable treatment option for children with CPP and marked growth deceleration during treatment with GnRHa alone.

Adult height in patients with permanent growth hormone deficiency with and without multiple pituitary hormone deficiencies.

CONTEXT: It has been reported that patients with multiple pituitary hormone deficiencies (MPHDs) achieve a greater final height, compared with patients with isolated GH deficiency (IGHD). However, the outcome of patients with permanent GH deficiency (GHD) has not yet been reported. OBJECTIVES: The objectives of the study were to evaluate and compare adult height data and the effect of spontaneous or induced puberty after long-term treatment with GH in young adults with either permanent IGHD or MPHD. DESIGN AND SETTING: This was a retrospective multicenter study conducted in university research hospitals and a tertiary referral endocrine unit. PATIENTS AND METHODS: Thirty-nine patients with IGHD (26 males, 13 females) and 49 with MPHD (31 males, 18 females), diagnosed at a median age of 7.7 and 6.9 yr, respectively, were reevaluated for GH secretion after adult height achievement (median age 17.6 and 19.8 yr). The diagnosis of permanent GHD was based on peak GH levels less than 3 microg/liter after an insulin tolerance test or peak GH levels less than 5 microg/liter after two different tests. Fifteen subjects had idiopathic GHD and seventy-three had magnetic resonance imaging evidence of congenital hypothalamic-pituitary abnormalities. Height sd score (SDS) was analyzed at diagnosis, the onset of puberty (either spontaneous or induced), and the time of GH withdrawal. RESULTS: The subjects with IGHD entered puberty at a median age of 12.6 yr (females) and 13.4 yr (males). Puberty was induced at a median age of 13.5 and 14.0 yr, respectively, in males and females with MPHD. Median height SDS at the beginning of puberty was similar in the IGHD and MPHD subjects. Total pubertal height gain was similar between patients with IGHD or MPHD. Median adult height was also not significantly different between IGHD and MPHD patients (males, 168.5 vs. 170.3 cm; females, 160.0 vs. 157.3 cm). The adult height SDS of the IGHD subjects was positively correlated with height at the time of diagnosis and with total pubertal height gain. Conversely, the adult height SDS of the MPHD subjects was positively correlated with both the duration of GH treatment and height SDS at the time of GHD diagnosis. CONCLUSIONS: Adult height in patients with permanent IGHD and spontaneous puberty is similar to adult height in patients with MPHD and induced puberty.

MANAGEMENT OF ENDOCRINE DISEASE: Long-term outcomes of the treatment of central precocious puberty.

GnRH analogues (GnRHa) are the treatment of choice for central precocious puberty (CPP), with the main objective to recover the height potential compromised by the premature fusion of growth cartilages. The aim of this review was to analyze long-term effects of GnRHa on height, body weight, reproductive function, and bone mineral density (BMD) in patients with CPP, as well as the potential predictors of outcome. Because randomized controlled trials on the effectiveness and long-term outcomes of treatment are not available, only qualified conclusions about the efficacy of interventions can be drawn. GnRHa treatment appears to improve adult height in girls with CPP, especially if diagnosed before the age of 6, whereas a real benefit in terms of adult height is still controversial in patients with the onset of puberty between 6 and 8 years of age. No height benefit was shown in patients treated after 8 years. Gonadal function is promptly restored in girls after cessation of treatment, and reproductive potential appears normal in young adulthood. Data are conflicting on the long-term risk of polycystic ovarian syndrome in both treated and untreated women. Fat mass is increased at the start of treatment but normalizes thereafter, and GnRHa itself does not seem to have any long-term effect on BMI. Similarly, analogue treatment does not appear to have a negative impact on BMD. Owing to the paucity of data available, no conclusions can be drawn on the repercussions of CPP and/or its treatment on the timing of menopause and on the health of the offspring.

Congenital Adrenal Hyperplasia: Unresolved Issues.

Congenital adrenal hyperplasia (CAH) describes a family of disorders that comes from enzymatic deficiencies in cortisol production, with 21-hydroxylase deficiency causing ∼90% of cases. Distinction is made between the severe classical form and milder nonclassical form of CAH. Molecular genetic analysis is used to confirm the hormonal diagnosis. A high rate of genotype-phenotype disconcordance has been found in 21-hydroxylase deficiency. The goal of treatment is to replace with synthetic glucocorticoids and mineralocorticoids and suppress adrenal androgen production. The treatment of patients affected with nonclassical CAH, particularly males, remains controversial. Variable synthetic glucocorticoids are used and new modes of glucocorticoid delivery are under investigation. To improve height, growth hormone and other adjuvant therapies are employed. Long-term outcomes of genital surgery using modern techniques in females affected with classical CAH continue to be investigated. Prenatal treatment with dexamethasone is available to avoid ambiguous genitalia in these females. Although studies have shown its safety to mother and fetus, prenatal treatment is still regarded as experimental. Currently, prenatal diagnosis of CAH can only be obtained through invasive methods. Recently, the detection of cell-free fetal DNA in maternal plasma has made it possible to make this diagnosis earlier and noninvasively.

Diagnosis of GH deficiency in the transition period: accuracy of insulin tolerance test and insulin-like growth factor-I measurement.

OBJECTIVE: A consensus exists that severe growth hormone deficiency (GHD) in adults is defined by a peak GH response to insulin-induced hypoglycemia (insulin tolerance test, ITT) of less than 3 microg/l based on a cohort of subjects with a mean age of 45 years. DESIGN AND METHODS: By considering one of the following two criteria for the diagnosis of probable permanent GHD, i.e. the severity of GHD (suggested by the presence of multiple pituitary hormone deficiencies (MPHD)) or the magnetic resonance (MR) imaging identification of structural hypothalamic-pituitary abnormalities, 26 patients (17 males, 9 females, mean age 20.8 +/- 2.3 years, range 17-25 years) were selected for re-evaluation of the GH response to ITT and their IGF-I concentration. Eight subjects had isolated GHD (IGHD) and 18 had MPHD. Normative data for peak GH were obtained after ITT in 39 healthy subjects (mean age 21.2 +/- 4.4 years, range 15.1-30.0 years) and the reference range for IGF-I was calculated using normative data from 117 healthy individuals. RESULTS: Mean peak GH response to ITT was significantly lower in the 26 patients (1.8+/-2.0 microg/l, range 0.1-6.1 microg/l) compared with the 39 controls (18.5 +/- 15.5 microg/l, range 6.1-84.0 microg/l; P < 0.0001). One subject with septo-optic dysplasia had a peak GH response of 6.1 microg/l that overlapped the lowest peak GH response obtained in normal subjects. There was an overlap for IGF-I SDS between subjects with IGHD and MPHD, as well as with normal controls. The diagnostic accuracy of a peak GH response of 6.1 microg/l showed a 96% sensitivity with 100% specificity. The maximum diagnostic accuracy with IGF-I SDS was obtained with a cut-off of -1.7 SDS (sensitivity 77%, specificity 100%) while an IGF-I < or = - 2.0 SDS showed a sensitivity of 62%. CONCLUSION: Our data show that the cut-off value of the peak GH response to ITT of less than 3 microg/l or 5 microg/l and of IGF-I of less than -2.0 SDS are too restrictive for the diagnosis of permanent GH deficiency in the transition period. We suggest that permanent GHD could be investigated more accurately by means of an integrated analysis of clinical history, the presence of MPHD, IGF-I concentration and the MR imaging findings of structural hypothalamic-pituitary abnormalities.

A novel mutation in the NR0B1 gene in a family with monozygotic twin sisters and congenital adrenal hypoplasia affected children.

OBJECTIVE: Congenital adrenal hypoplasia (CAH) is a rare disorder that can be inherited in an X-linked or autosomal recessive pattern. CAH is frequently associated with hypogonadotropic hypogonadism (HHG) with absent or arrested puberty and impaired fertility caused by abnormalities in spermatogenesis. It is estimated that more than 50% of boys with idiopathic adrenal insufficiency have mutations in the NR0B1 gene product, DAX1. CASE REPORT: The proband is a young boy born after an uneventful pregnancy and delivery to non-consanguineous parents. At age 4 years and 4 months he came to our attention because of severe vomiting, abdominal pain, dehydration, and asthenia. The proband underwent a detailed clinical investigation including genetic testing. Sequencing analysis of the NR0B1 gene coding region from the affected child revealed a novel hemizygous deletion [c.385delC; p.(Leu129Cysfs*135)]. This mutation was also present in the heterozygous healthy mother and in her twin sister and in the first cousin of the proband. Monozygosity of the twin sisters was demonstrated. This suggests a de novo mutation and gonadal mosaicism for the deletion. CONCLUSIONS: Adrenal hypoplasia typically presents as adrenal insufficiency during the first few months of life, however, not necessarily as shown by our index case. HHG is thought to affect all NR0B1 mutated patients who reach puberty and, as understanding of the disease has improved, more of these patients survive while presenting different features of the disease, this emphasizing the value of genetic testing in boys with primary adrenal insufficiency and suspected X-linked CAH.

Spontaneous growth hormone (GH) secretion is not directly affected by ghrelin in either short normal prepubertal children or children with GH neurosecretory dysfunction.

Ghrelin, a specific endogenous ligand for the GH secretagogue receptor, stimulates GH secretion in humans when given in pharmacological amounts. Under physiological conditions, however, it is controversial whether ghrelin affects GH secretion and vice versa. No studies have reported on the relationship between daily ghrelin and GH secretion in children. Therefore, plasma ghrelin and GH concentrations over a 24-h period were studied in 10 prepubertal short normal children (five females and five males) to determine the potential relationship between the secretion of these two hormones. Furthermore, five prepubertal patients (two females and three males) with GH neurosecretory dysfunction (GHNSD) were studied in the same way to assess potential alterations in ghrelin secretion in a condition associated with distinct GH changes. No gender difference in ghrelin spontaneous secretion was detected in either short normal children or GHNSD patients, and in both male and female subjects, ghrelin was secreted in a pulsatile and circadian fashion, with a nocturnal surge. Twenty-four-hour secretion and daytime ghrelin secretion of short normal children were similar to those in GHNSD patients, whereas nighttime hormone secretion in the latter group was significantly greater than that in short normal children. The cross-correlation of 24-h ghrelin and GH levels revealed significant positive and negative correlations, which were similar in the two groups examined. The positive one, with GH leading ghrelin, might reflect a somatostatin (SMS)-mediated inhibitory effect on both GH and ghrelin secretion (low SMS levels are followed by high GH and ghrelin levels, and vice versa). The negative correlation, with ghrelin leading GH, might again reflect the positive effect of ghrelin on SMS, as shown in both animal and human studies. In conclusion, the results of the present study indicate that ghrelin secretion in prepubertal children is pulsatile and is not sexually dimorphic. Although the parallelism of ghrelin and GH dynamics hints at the potential relevance of endogenous ghrelin as a promoter of GH release, our data do not support this hypothesis. We suggest that the interactions of ghrelin and GH are the result of SMS action. SMS inhibits GH secretion not only by a direct effect on the pituitary and by inhibiting hypothalamic GHRH, but also through the suppression of ghrelin release.

Interactions of leptin, GH, and cortisol in normal children.

Leptin is the product of the ob gene located in humans on chromosome 7q31.3. It is a 16-kDa protein named after the Greek "leptos," meaning lean, to indicate the function that this adipocyte-secreted protein was thought to have. Since its discovery, in fact, most of the research focused on the role of leptin in body-weight regulation, aiming to elucidate the pathophysiology of human obesity. However, more and more data show that leptin is not only important in the regulation of food intake and energy balance, but it also functions as a neuroendocrine hormone. It is involved in glucose metabolism, as well as in normal sexual maturation and reproduction, and interacts with the hypothalamic-pituitary-adrenal (HPA) and the growth hormone (GH) axes.

Leuteinizing hormone responses to leuprolide acetate discriminate between hypogonadotropic hypogonadism and constitutional delay of puberty.

OBJECTIVE: To assess if leuprolide acetate stimulation discriminates between hypogonadotropic hypogonadism (HH) and constitutional delay of puberty (CDP) in males. DESIGN: Case-control study. SETTING: Patients attending an academic research environment. PATIENTS: Only male patients were studied: 10 with HH (group 1, age 16.5 +/- 6.0 years), 8 prepubertal with CDP (group 2, age 14.3 +/- 1.2 years), 6 healthy prepubertal (group 3, age 9.5 +/- 3.3 years), and 8 healthy late-pubertal (group 4, age 15.1 +/- 3.1 years). INTERVENTION(S): Blood samples were obtained after an overnight fast. Leuprolide acetate was then administered SC, and blood samples were drawn at 0, 30, 60, 120, 180 minutes, and 6 and 24 hours after stimulation. MAIN OUTCOME MEASURE(S): Clinical follow-up evaluations of data and serum levels of LH, FSH, 17-hydroxyprogesterone, and testosterone. RESULT(S): Basal LH levels were similar in groups 1 through 3 and differed significantly from those in group 4. Peak serum LH levels were significantly higher in CDP compared with HH (8.9 +/- 1.4 vs. 1.4 +/- 0.2 IU/L). Baseline FSH levels were significantly higher only in pubertal boys (versus the HH group); peak levels did not differ among the groups. Basal and peak testosterone levels were significantly higher only in the control pubertal group when compared to the other groups; peak 17-hydroxyprogesterone concentrations were significantly higher in pubertal controls compared with HH and CDP. CONCLUSION(S): Peak LH responses clearly discriminate HH from CDP. Timing for blood sampling should be fixed at 0, 60, 120, 180 minutes after stimulation.