BackgroundThe consensus documents published to date on hereditary angioedema with C1 inhibitor deficiency (C1‐INH‐HAE) have focused on adult patients. Many of the previous recommendations have not been adapted to pediatric patients. We intended to produce consensus recommendations for the diagnosis and management of pediatric patients with C1‐INH‐HAE.MethodsDuring an expert panel meeting that took place during the 9th C1 Inhibitor Deficiency Workshop in Budapest, 2015 (www.haenet.hu), pediatric data were presented and discussed and a consensus was developed by voting.ResultsThe symptoms of C1‐INH‐HAE often present in childhood. Differential diagnosis can be difficult as abdominal pain is common in pediatric C1‐INH‐HAE, but also commonly occurs in the general pediatric population. The early onset of symptoms may predict a more severe subsequent course of the disease. Before the age of 1 year, C1‐INH levels may be lower than in adults; therefore, it is advisable to confirm the diagnosis after the age of one year. All neonates/infants with an affected C1‐INH‐HAE family member should be screened for C1‐INH deficiency. Pediatric patients should always carry a C1‐INH‐HAE information card and medicine for emergency use. The regulatory approval status of the drugs for prophylaxis and for acute treatment is different in each country. Plasma‐derived C1‐INH, recombinant C1‐INH, and ecallantide are the only agents licensed for the acute treatment of pediatric patients. Clinical trials are underway with additional drugs. It is recommended to follow up patients in an HAE comprehensive care center.ConclusionsThe pediatric‐focused international consensus for the diagnosis and management of C1‐INH‐HAE patients was created.

Background Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient or clinician reported sick day episodes (SDE) is less clear. Methods Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analysed to examine the clinical factors associated with SDE and AC. Results 518 children with a median of 11 children (range 1, 53) per center had 5,388 visits evaluated over a total of 2,300 patient years. The median number of AC and SDE per patient year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1,544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1,105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (p<0.001), respectively and the median AC per patient year was 0 (0, 2.2) vs 0 (0, 3.0) (p=0.43), respectively. Conclusions The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardise the definition of SDE.

We investigated whether an altered individual glucocorticoid sensitivity due to particular glucocorticoid receptor single-nucleotide polymorphisms (SNPs) (N363S, ER22/23EK, and Bcl-1) influences the susceptibility to steroid-related toxicities, prognostic factors, and survival rates in children with acute lymphoblastic leukemia. In total, 346 pediatric patients with acute lymphoblastic leukemia were enrolled in our study. Their carrier status was investigated by allele-specific polymerase chain reaction analysis. Clinical and laboratory signs of glucocorticoid-related toxicities, day-8 prednisone response, 5-year event-free survival, and 5-year overall survival rates were analyzed and compared retrospectively. Hepatotoxicity occurred significantly more often in 363S carriers (P=0.004), and glucose metabolism abnormalities were more common in 363S carriers (P=0.001), but did not occur in patients with the ER22/23EK SNP. Hypertension and central nervous system/behavioral changes did not occur in patients with the ER22/23EK SNP. None of the patients with the N363S SNP, the ER22/23EK polymorphism, or the GG genotype for the Bcl-1 polymorphism had a poor prednisone response. The 363S carriers had significantly better 5-year event-free survival (P=0.012) and 5-year overall survival (P=0.013) rates compared with noncarriers. The Bcl-1 SNP was not associated with any of the toxicities investigated or survival. Children with the N363S polymorphism in the glucocorticoid receptor gene were more prone to steroid-related toxicities, whereas those with the ER22/23EK polymorphism were less susceptible. Children with the N363S polymorphism may have more favorable survival rates.

Objective: Congenital adrenal hyperplasia (CAH) shows a range of severity which is explained in part by the different mutations of the CYP21 gene. To better understand the incomplete concordance between genotype and phenotype in CAH the role of the sensitizing N363S polymorphism of the glucocorticoid receptor (GR) was examined in CAH patients. Design: CAH patients were screened for N363S. Laboratory findings and clinical characteristics of carriers and non-carriers were analyzed retrospectively. Methods: The CYP21 gene of 200 CAH patients was analyzed by allele-specific PCR. The GR gene was tested for N363S by PCR followed by restriction fragment length polymorphism. Antropometric data (height, weight), degree of intrauterine virilization, hormone concentrations (17-OH-progesterone, dehydroepiandrosterone (DHEA), aldosterone, testosterone, plasma renin activity), substitution doses and clinical course were analyzed. Results: The carrier frequency of N363S in CAH patients was equivalent to that of the general Hungarian population (6% vs 7.8%). Interestingly, none of the non-classical CAH (NC-CAH) patients were carriers of the polymorphism. Carrier girls had milder genital virilization than mutation-matched non-carrier controls. There was no significant difference between the carriers and non-carriers in either the substitution doses, the hormonal, or the auxiological parameters. Conclusions: The association of sensitizing the GR variant with impaired cortisol production in CAH might be compensatory in mild NC-CAH and may prevent severe intrauterine virilization in classical form. Although the exact role of N363S in extrauterine life should be further investigated, the consideration of certain genetic polymorphisms of CAH patients may lead to better, individualized therapeutic regimes.European Journal of Endocrinology 154 859-864

Objective: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. Design: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. Methods: Data was collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 – 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement was analyzed from 4174 patient visits. Results: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0 – 14.5) mg/ m2/ day at age 1 - 8 years and the highest dose of 14.0 (11.6 - 17.4) mg/ m2/ day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (p<0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. Conclusions: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.