The fetal hypothalamus-pituitary gonadal (HPG) axis begins to function during mid-gestation but its activity decreases during late pregnancy due to the suppressive effects of placental estrogens. ...Placental hormones drop immediately after birth, FSH and LH surge at around 1 week and peak between 1 and 3 months of life. The HPG axis is activated in both sexes, but a sexual dimorphism is evident with higher LH values in boys, while FSH prevails in girls. Both gonadotrophins decline in boys by around 6 months of age. In girls, LH declines at the same time as in boys, while FSH persists elevated up to 3 or 4 years of age. As a result of gonadotropin activation, testicular testosterone increases in males and ovarian estradiol rises in females. These events clinically translate into testicular and penile growth in boys, enlargement of uterus and breasts in girls. The functional impact of HPG axis activity in infancy on later reproductive function is uncertain. According to the perinatal programming theory, this period may represent an essential programming process. In boys, long-term testicular hormonal function and spermatogenesis seem to be, at least in part, regulated by minipuberty. On the contrary, the role of minipuberty in girls is still uncertain. Recently, androgen exposure during minipuberty has been correlated with later sex-typed behavior. Premature and/or SGA infants show significant differences in postnatal HPG axis activity in comparison to full-term infants and the consequences of these differences on later health and disease require further research. The sex-dimorphic HPG activation during mid-gestation is probably responsible for the body composition differences observed ad birth between boys and girls, with boys showing greater total body mass and lean mass, and a lower proportion of fat mass. Testosterone exposure during minipuberty further contributes to these differences and seems to be responsible for the significantly higher growth velocity observed in male infants. Lastly, minipuberty is a valuable "window of opportunity" for differential diagnosis of disorders of sex development and it represents the only time window before puberty when congenital hypogonadism can be diagnosed by the simple analysis of basal gonadotropin and gonadal hormone levels.
In 1882, von Recklinghausen described a group of patients with multiple tumors arising from the 'endoneurium' of peripheral nerves, and called them 'neurofibromas'. The term von Recklinghausen ...disease was used up to the end of the 20th century, when the gene of neurofibromatosis (NF1) was cloned on chromosome 17q11.2. The gene product is a cytoplasmic protein termed neurofibromin, regulating proliferation and maturation of both glial and neuronal progenitors during embryogenesis. Loss of neurofibromin function determines the hyperactivation of the proto-oncogene RAS, leading to an increased risk of tumor formation, predominantly affecting the skin, bone and the nervous system. NF1 is clinically and genetically distinct from neurofibromatosis type 2, characterized by bilateral vestibular schwannomas and other nervous system tumors. An increased incidence of central precocious puberty, diencephalic syndrome, GH deficiency and GH hypersecretion has been described in NF1 children. These conditions are commonly complications of optic pathway gliomas (OPG) involving the hypothalamic and sellar region. Nevertheless, these endocrine disorders have been observed also in children without evidence of OPG at magnetic resonance imaging. Clinical and laboratory follow-up is crucial in all children with NF1, particularly in those with an OPG, aiming at the early identification of signs suggestive of secondary endocrine alterations.
X-linked adrenoleukodystrophy (X-ALD; OMIM:300100) is a progressive neurodegenerative disorder caused by a congenital defect in the ATP-binding cassette transporters sub-family D member 1 gene ...(ABCD1) producing adrenoleukodystrophy protein (ALDP). According to population studies, X-ALD has an estimated birth prevalence of 1 in 17.000 subjects (considering both hemizygous males and heterozygous females), and there is no evidence that this prevalence varies among regions or ethnic groups. ALDP deficiency results in a defective peroxisomal β-oxidation of very long chain fatty acids (VLCFA). As a consequence of this metabolic abnormality, VLCFAs accumulate in nervous system (brain white matter and spinal cord), testis and adrenal cortex. All X-ALD affected patients carry a mutation on the ABCD1 gene. Nevertheless, patients with a defect on the ABCD1 gene can have a dramatic difference in the clinical presentation of the disease. In fact, X-ALD can vary from the most severe cerebral paediatric form (CerALD), to adult adrenomyeloneuropathy (AMN), Addison-only and asymptomatic forms. Primary adrenal insufficiency (PAI) is one of the main features of X-ALD, with a prevalence of 70% in ALD/AMN patients and 5% in female carriers. The pathogenesis of X-ALD related PAI is still unclear, even if a few published data suggests a defective adrenal response to ACTH, related to VLCFA accumulation with progressive disruption of adrenal cell membrane function and ACTH receptor activity. The reason why PAI develops only in a proportion of ALD/AMN patients remains incompletely understood. A growing consensus supports VLCFA assessment in all male children presenting with PAI, as early diagnosis and start of therapy may be essential for X-ALD patients. Children and adults with PAI require individualized glucocorticoid replacement therapy, while mineralocorticoid therapy is needed only in a few cases after consideration of hormonal and electrolytes status. Novel approaches, such as prolonged release glucocorticoids, offer potential benefit in optimizing hormonal replacement for X-ALD-related PAI. Although the association between PAI and X-ALD has been observed in clinical practice, the underlying mechanisms remain poorly understood. This paper aims to explore the multifaceted relationship between PAI and X-ALD, shedding light on shared pathophysiology, clinical manifestations, and potential therapeutic interventions.
At the end of 2019, an emerging atypical pneumonia called COVID-19 (coronavirus disease 2019), caused by the novel coronavirus defined as SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), ...was first reported. COVID-19 rapidly expanded leading to an epidemic in China, followed by a global pandemic during the year 2020. In few weeks Italy was assaulted by a severe health emergency, constraining the Italian government to put in place extraordinary restrictive measures, such as school closures and a strict lockdown extended to the entire country at the beginning of March 2020. Since the beginning of lockdown, the Endocrinology Unit of Bambino Gesù Children's Hospital has recorded a rapid increase of the outpatient consultations for suspected precocious or early puberty. We have now retrospectively analyzed all the consultations recorded in the database of our outpatient clinic from March to September 2020, and compared them with the consultations recorded in the same database from March to September 2019. Our preliminary data suggest a significant increase of precocious puberty cases in girls during the first period of COVID-19 pandemic. Further investigations in larger cohorts of children are needed in order to correlate the observed increase of precocious puberty with specific pathogenic factors.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Since the outbreak of COVID-19 pandemic, several centers of pediatric endocrinology worldwide have observed a significant increase in the number of girls presenting with precocious or early puberty. ...We aimed to compare the incidence rates of female precocious puberty before and during the different phases of COVID-19 pandemic.
We have retrospectively analyzed all the consultations recorded in the outpatient clinic database of the Endocrinology Unit of Bambino Gesù Children's Hospital, Rome, Italy, from the lockdown start in March 2020 up to September 2020, in comparison with the consultations recorded in the same months of 2019, 2021 and 2022. Age, height, weight, body mass index, Tanner's pubertal stage and bone age at presentation, birth weight, ethnicity, family history of central precocious puberty (CPP), maternal age at menarche, history of adoption were retrieved from clinical records. Serum levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) both at baseline and after gonadotropin-releasing hormone (GnRH) stimulation, and basal estradiol levels were collected.
In 2019, 78 girls with suspected precocious puberty were referred for endocrinological consultation, compared to 202 girls in 2020, 158 girls in 2021 and 112 girls in 2022. A significant increase in the proportion of girls diagnosed with rapidly progressive CPP was observed in 2020, compared to 2019 (86/202
18/78, p<0.01). In the following periods of 2021 and 2022, a gradual decrease in the number of cases of progressive CPP was evident, so much that the number of cases was not significantly different from that observed in 2019 (56/158 in 2021 and 35/112 in 2022, p=0.054 and p=0.216 respectively, compared to 2019).
Our research suggests that drastic lifestyle changes, such as those imposed by COVID-19 lockdown, and the consequent stress may affect the regulation of pubertal timing. The remarkable increase in CPP cases observed during the 2020 first pandemic wave seems to be reduced in 2021 and 2022, concurrently with the progressive resumption of daily activities. These data seem to support the hypothesis of a direct relationship between profound life-style changes related to the pandemic and the rise in precocious puberty cases.
Despite the optimization of replacement therapy, adrenal crises still represent life-threatening emergencies in many children with adrenal insufficiency.
We summarized current standards of clinical ...practice for adrenal crisis and investigated the prevalence of suspected/incipient adrenal crisis, in relation to different treatment modalities, in a group of children with adrenal insufficiency.
Fifty-one children were investigated. Forty-one patients (32 patients <4 yrs and 9 patients >4 yrs) used quartered non-diluted 10 mg tablets. Two patients <4 yrs used a micronized weighted formulation obtained from 10 mg tablets. Two patients <4 yrs used a liquid formulation. Six patients >4 yrs used crushed non-diluted 10 mg tablets. The overall number of episodes of adrenal crisis was 7.3/patient/yr in patients <4yrs and 4.9/patient/yr in patients >4 yrs. The mean number of hospital admissions was 0.5/patient/yr in children <4 yrs and 0.53/patient/yr in children >4 yrs. There was a wide variability in the individual number of events reported. Both children on therapy with a micronized weighted formulation reported no episode of suspected adrenal crisis during the 6-month observation period.
Parental education on oral stress dosing and switching to parenteral hydrocortisone when necessary are the essential approaches to prevent adrenal crisis in children.
Small for gestational age (SGA) is associated with an increased risk of non-alcoholic fatty liver disease (NAFLD). Our aim was to investigate the correlation of birthweight with the severity of liver ...damage in a large cohort of children with NAFLD.
Two hundred and eighty-eight consecutive Caucasian Italian overweight/obese children with biopsy-proven NAFLD were included in the study. We examined the relative association of each histological feature of NAFLD with metabolic alterations, insulin-resistance, I148M polymorphism in the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene, and birthweight relative to gestational age.
In the whole NAFLD cohort, 12.2% of patients were SGA, 62.8% appropriate for gestational age (AGA), and 25% large for gestational age (LGA). SGA children had a higher prevalence of severe steatosis (69%) and severe portal inflammation (14%) compared with the AGA and LGA groups. Notably, severe steatosis (>66%) was decreasing from SGA to AGA and LGA, whereas the prevalence of moderate steatosis (33-66%) was similar in three groups. The prevalence of type 1 NAFLD is higher in the LGA group with respect to the other two groups (25% vs.5.2% vs.9.4%), whereas the SGA group shows a higher prevalence of overlap type (85.8%) with respect to the LGA group (51.4%) but not compared with the AGA group (75%). At multivariable regression analysis, SGA at birth increased fourfold the likelihood of severe steatosis (odds ratio (OR) 4.0, 95% confidence interval (CI) 1.43-10.9, P=0.008) and threefold the likelihood of NAFLD Activity Score (NAS)≥5 (OR 2.98, 95% CI 1.06-8.33, P=0.037) independently of homeostasis model assessment of insulin resistance and PNPLA3 genotype. The PNPLA3-CC wild-type genotype was the strongest independent predictor of the absence of significant fibrosis (OR 0.26, 95% CI 0.13-0.52, P=<0.001).
In children with NAFLD, the risk of severe steatosis is increased by SGA at birth, independent of and in addition to other powerful risk factors (insulin-resistance and I148M variant of the PNPLA3 gene).
No data are available on insulin clearance (ClI) trends during the pubertal transition. The aim of this study was to investigate in 973 youths with obesity whether ClI in fasting and post-oral ...glucose challenge (OGTT) conditions varies at the pubertal transition in relation to the severity of obesity and the presence of steatosis liver disease (SLD). The severity of obesity was graded according to the Centers for Disease Control. SLD was graded as absent, mild and severe based on alanine amino transferase levels. ClI was defined as the molar ratio of fasting C-peptide to insulin and of the areas under the insulin to glucose curves during an OGTT. In total, 35% of participants were prepubertal, 72.6% had obesity class II, and 52.6% had mild SLD. Fasting ClI (nmol/pmol × 10−2) was significantly lower in pubertal 0.11 (0.08–0.14) than in prepubertal individuals 0.12 (0.09–0.16) and higher in class III 0.15 (0.11–0.16) than in class I obesity 0.11 (0.09–0.14). OGTT ClI was higher in boys 0.08 (0.06–0.10) than in girls 0.07 (0.06–0.09); in prepubertal 0.08 (0.06–0.11) than in pubertal individuals 0.07 (0.05–0.09); in class III 0.14 (0.08–0.17) than in class I obesity 0.07 (0.05–0.10); and in severe SLD 0.09 (0.04–0.14) than in no steatosis 0.06 (0.04–0.17). It was lower in participants with prediabetes 0.06 (0.04–0.07). OGTT ClI was lower in youths with obesity at puberty along with insulin sensitivity and greater secretion. The findings suggest that the initial increase in ClI in youth with severe obesity and SLD is likely to compensate for hyperinsulinemia and its subsequent decrease at the onset of prediabetes and other metabolic abnormalities.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Abstract
Context
Primary adrenal insufficiency (PAI) is a rare and potentially life-threatening condition that is poorly characterized in children.
Objective
To describe causes, presentation, ...auxological outcome, frequency of adrenal crisis and mortality of a large cohort of children with PAI.
Patients and Methods
Data from 803 patients from 8 centers of Pediatric Endocrinology were retrospectively collected.
Results
The following etiologies were reported: 85% (n = 682) congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD); 3.1% (n = 25) X-linked adrenoleukodystrophy; 3.1% (n = 25) autoimmune polyglandular syndrome type 1; 2.5% (n = 20) autoimmune adrenal insufficiency; 2% (n = 16) adrenal hypoplasia congenital; 1.2% (n = 10) non-21-OHD CAH; 1% (n = 8) rare syndromes; 0.6% (n = 5) familial glucocorticoid deficiency; 0.4% (n = 3) acquired adrenal insufficiency; 9 patients (1%) did not receive diagnosis. Since 21-OHD CAH has been extensively characterized, it was not further reviewed. In 121 patients with a diagnosis other than 21-OHD CAH, the most frequent symptoms at diagnosis were fatigue (67%), hyperpigmentation (50.4%), dehydration (33%), and hypotension (31%). Elevated adrenocorticotropic hormone (96.4%) was the most common laboratory finding followed by hyponatremia (55%), hyperkalemia (32.7%), and hypoglycemia (33.7%). The median age at presentation was 6.5 ± 5.1 years (0.1-17.8 years) and the mean duration of symptoms before diagnosis was 5.6 ± 11.6 months (0-56 months) depending on etiology. Rate of adrenal crisis was 2.7 per 100 patient-years. Three patients died from the underlying disease. Adult height, evaluated in 70 patients, was −0.70 ± 1.20 standard deviation score.
Conclusions
We characterized one of the largest cohorts of children with PAI aiming to improve the knowledge on diagnosis of this rare condition.
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