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Background:In boys with suspected partial androgen insensitivity syndrome (PAIS), systematic evidence that supports the long-term prognostic value of identifying a mutation in the androgen receptor gene (AR) is lacking.Objective:To assess the clinical characteristics and long-term outcomes in young men with suspected PAIS in relation to the results of ARanalysis.Methods:Through the International Disorders of Sex Development Registry, clinical information was gathered on young men suspected of having PAIS (n = 52) who presented before the age of 16 years and had genetic analysis of AR.Results:The median ages at presentation and at the time of the study were 1 month (range, 1 day to 16 years) and 22 years (range, 16 to 52 years), respectively. Of the cohort, 29 men (56%) had 20 different ARmutations reported. At diagnosis, the median external masculinization scores were 7 and 6 in cases with and without ARmutation, respectively (P= .9), and median current external masculinization scores were 9 and 10, respectively (P= .28). Thirty-five men (67%) required at least one surgical procedure, and those with a mutation were more likely to require multiple surgeries for hypospadias (P= .004). All cases with an ARmutation had gynecomastia, compared to 9% of those without an ARmutation. Of the six men who had a mastectomy, five (83%) had an ARmutation.Conclusions:Boys with genetically confirmed PAIS are likely to have a poorer clinical outcome than those with XY DSD, with normal T synthesis, and without an identifiable ARmutation. Routine genetic analysis of ARto confirm PAIS informs long-term prognosis and management.

OBJECTIVE: To evaluate whether genotype differences can explain the clinical variability of non-classical steroid 21-hydroxylase deficiency (NC21-OHD) and to determine if genotype is related to ethnic origin. DESIGN: Genotyping for mutations in the steroid 21-hydroxylase (CYP21) gene was performed in 45 unrelated Israeli Jewish patients (nine males) with NC21-OHD (60min 17-hydroxyprogesterone (17-OHP), 45-386nmol/l) who were referred for evaluation of postnatal virilization or true precocious/early puberty. Eleven siblings diagnosed through family screening were genotyped as well. METHODS: Patients were divided by genotype into three groups: (A) homozygous or compound heterozygous for the mild mutations (V281L or P30L) (n=29; eight males); (B) compound heterozygous for one mild and one severe mutation (Q318X, I2 splice, I172N) (n=12; no males); (C) mild mutation detected on one allele only (n=4; one male; peak 17-OHP 58-151nmol/l). We then related the genotype to the ethnic origin, clinical phenotype and hormone level. Since group C was very small, comparisons were made between groups A and B only. RESULTS: At diagnosis, group B tended to be younger (5. 8+/-3.0 vs 8.1+/-4.3 years, P=0.09), had greater height SDS adjusted for mid-parental height SDS (1.6+/-1.1 vs 0.7+/-1.4, P=0.034), tended to have more advanced bone age SDS (2.9+/-1.5 vs 1.7+/-2.1, P=0.10) and had a higher peak 17-OHP level in response to ACTH stimulation (226+/-92 vs 126+/-62nmol/l, P<0.01). Group B also had pubarche and gonadarche at an earlier age (5.1+/-2.4 vs 7.4+/-2.2 years, P<0.01 and 7.4+/-1.8 vs 9.9+/-1.4 years, P<0.001, respectively) and a higher rate of precocious puberty (50 vs 17%, P=0.04). Stepwise logistic regression analysis (excluding males) yielded age at gonadarche as the most significant variable differentiating the two groups, with a positive predictive value of 86% for a cut-off of 7.5 years. CONCLUSIONS: The findings suggest that genotype might explain some of the variability in the phenotypic expression of NC21-OHD. Compound heterozygotes for one mild and one severe mutation have a higher peak 17-OHP associated with pubarche and gonadarche at an earlier age and more frequent precocious puberty. Hence, the severity of the enzymatic defect might determine the timing and pattern of puberty.

OBJECTIVE: To determine the feasibility of using the combined oral clonidine and the short-ACTH test instead of the sometimes dangerous insulin-induced hypoglycemia test as a screening procedure, for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children with growth retardation. DESIGN: Evaluative study. METHOD: Seventy-three children (52 males) aged 11+/-3 years with attenuated growth (group 1) were tested by combined clonidine (150 microg/m(2)) and short-ACTH test (either the standard 250 microg or the low-dose 1 microg/1. 73 m(2)). Thirty-one children received no pretreatment (nonprimed) (subgroup 1NP), and 42 were primed with ethynylestradiol 40 microg/m(2)/day two days before testing (subgroup 1P). The control group for the short-ACTH test (group 2) consisted of 42 children and adolescents (13 males) aged 12+/-3 years with early or accelerated puberty or premature closure of epiphyses, who received ACTH only (21 standard, 21 low-dose) with no evidence of adrenal or pituitary pathology. The peak GH response was compared between the primed and the nonprimed group 1 subjects, and the cortisol levels were compared between the combined test subgroups and the controls. The peak pass level for growth hormone was 10 ng/ml; the peak pass level for cortisol was 520 nmol/l. RESULTS: Sixty-four of the 73 children in group 1 (87.7%) showed a growth hormone level of >/=10 ng/ml on the first stimulation test, including 26/31 (84%) nonprimed and 38/42 (90.5%) primed. Of the 9 patients who failed the first clonidine test, 4 also failed the second, primed test, including 1/5 nonprimed patients (20%) and 3/4 primed patients (75%). This yielded a GH deficiency/insufficiency rate of 5.5% and a rather low false-positive rate of 13.3% (4/30) for the nonprimed subjects and 2. 6% (1/39) for the primed subjects. Peak 30-min cortisol in response to ACTH stimulation was similar in the patients who underwent the 250 microg or the 1 microg test within each group (subgroup 1NP, subgroup 1P and group 2); therefore, the results for the two tests were considered together. Compared with group 2, subgroup 1NP patients had a similar 30-min cortisol response (P=NS), and subgroup 1P patients had a much higher response (P<0.05) (group 2=690+/-145 nmol/l, subgroup 1NP=772+/-195 nmol/l, subgroup 1P=934+/-209 nmol/l). However, there was no significant difference in the increment in cortisol response between the three groups. CONCLUSIONS: Our results suggest that the combined clonidine-short-ACTH test is a reliable and safe tool for the simultaneous assessment of growth hormone reserve and hypothalamic-pituitary-adrenal axis integrity in children.

Persistent hyperinsulinaemic hypoglycaemia of infancy (PHHI) is a genetic disorder which causes severe hypoglycaemia in the neonate. The beta cells fail to respond to changes in blood glucose levels in all the stages of the disease, which often ends with NIDDM. Fasting insulin, intact proinsulin and des 31,32 split proinsulin levels were measured in PHHI patients with active disease, patients after partial pancreatectomy, and those in clinical remission. All but one of the pancreatectomized patients developed diabetes and were hyperglycaemic on evaluation. Fasting insulin was comparable in pancreatectomized and medically treated patients. Des 31,32 split proinsulin levels were much higher in pancreatectomized compared to non-pancreatectomized patients (10.7 ± 2.5 vs 3.4 ± 0.8 pmol/l, p= 0.001) and age-matched control subjects (3.8 ± 1.4 pmol/l, p= 0.018). Also the ratio of des 31,32 split proinsulin to total insulin plus proinsulin-like peptides was higher in pancreatectomized patients (18.7 ± 2.8 vs 7.2 ± 0.8 % in non-pancreatectomized patients, p= 0.001, and 6.8 ± 2.1 % in normal control subjects, p= 0.004). Furthermore, des 31,32 split proinsulin was the dominating species of proinsulin-like molecules in the pancreatectomized patients (62.7 ± 1.6 % vs 45.5 ± 3.8 %, and 49.0 ± 3.2 % in non-pancreatectomized patients and control subjects, respectively, p= 0.001 and p= 0.0002). Intact proinsulin levels, and the proinsulin percentage, tended to be higher in pancreatectomized patients; however, the differences did not reach statistical significance. All parameters were similar in non-pancreatectomized patients and age-matched control subjects. Subgroup analysis showed comparable proinsulin-like peptide levels in patients with active disease and those in apparent clinical remission. Fasting levels of insulin and proinsulin-like peptides were also measured in a larger group of healthy children and young adults. Insulin and des 31,32 split proinsulin increased with age, the differences being most prominent when the young age group (0–8 years) was compared to the older groups (8–16 and > 16 years). The fasting levels of plasma insulin were correlated with those of intact proinsulin and des 31,32 split proinsulin (r= 0.82 and 0.81, respectively). Fasting insulin, intact proinsulin and des 31,32 split proinsulin were correlated with BMI (r= 0.55, 0.56 and 0.53, respectively). In summary, relative hyperproinsulinaemia was noted only in PHHI patients with increased secretory demand following pancreatectomy, but not in patients with active disease or those in spontaneous clinical remission. These findings suggest that abnormal proinsulin processing is not an intrinsic feature of PHHI despite the severe beta-cell dysfunction. [Diabetologia (1996) 39: 1338–1344]

Many women with 21-hydroxylase (21-OH)-deficient nonclassic adrenal hyperplasia (NCAH) carry at least one allele containing a severe mutation of CYP21, and as such are at risk for giving birth to an infant having classic adrenal hyperplasia (CAH). Infants with NCAH typically are asymptomatic at birth, in contrast to those with CAH, but they do develop symptoms of hyperandrogenism later in childhood or as adults. This international multicenter study, conducted both retrospectively and prospectively, was an attempt to determine how often mothers with 21-OH-deficient NCAH bear infants having CAH or NCAH. The 101 women entering the study had a total of 203 pregnancies that could be evaluated. Fourteen tertiary referral centers in nine countries participated in the study. The diagnosis of 21-OH-deficient NCAH was based on a baseline or post-ACTH level of 17-hydroxyprogesterone exceeding 10 ng/mL. Where feasible, the offspring underwent genotypic analysis.

Objective: To assess the prevalence and risk factors of adrenal insufficiency (AI) in children after kidney or liver transplantation, hospitalized for a physiological stress episode, and to identify patients that might be at risk of adrenal crises by clinical and laboratory parameters at admission.Patients and Methods: Adrenal function was prospectively evaluated by standard (250 µg) adrenocorticotropin test in 48 kidney or liver transplant pediatric recipients admitted for a physiological stress episode. Data on cumulative steroid treatment and clinical and laboratory findings were collected.Results: Thirty-two patients were receiving longterm corticosteroids treatment and 16 were not. Al was diagnosed in 11 patients: 10 (31.3%) on long-term treatment and in one (6.25%) untreated. The only risk factor for AI was a cumulative dose of corticosteroids of >0.15mg/kg/d in the last 6 months (p=0.02, odds ratio of 6.67 (95%CI: 0.97- 45.79)). There was no correlation between clinical or laboratory signs of adrenal crisis on admission and the presence of AI. None of the patients with AI who didn't receive stress dose (n=8) developed adrenal crisis.Conclusion: AI is present in about third of children receiving prolonged corticosteroid treatment after kidney or liver transplantation. Clinical parameters on admission can not reliably identify patients with AI. Universal administration of a stress dose during physiological stress is not required, and careful selection of patients who do require steroid stress dose is recommended.

The aims of the 2021 European Training Requirements (ETR) in Paediatric Endocrinology and Diabetes (PED) are to (1) provide standards to harmonize training programmes in PED between different European countries, (2) establish clearly defined standards of knowledge and skills required to practice PED at the tertiary care level, (3) foster the development of a network of competent tertiary care centres for PED in Europe and globally, and (4) improve the quality of care for children and adolescents requiring PED services. This ETR in PED specifies the requirements for training institutions, trainers, and trainees. It also provides the detailed syllabus/core content that trainees are expected to achieve in order to become competent independent clinicians in PED. References to consensus guidelines produced and/or endorsed by ESPE are included. The target users are trainees in PED, trainers, and all involved with quality assurance and accreditation. The process to develop and approve this 2021 ETR has been rigorous and involved trainees and consultants in paediatric and adult Endocrinology, ESPE (Syllabus Task Force, Education and Training Committee, Council), European Academy of Paediatrics (Tertiary Care Council, Assembly), European Board of Paediatrics, and Union of European Medical Specialists. Implementing the ETR will complement professional regulatory requirements for postgraduate training in PED in different countries and allow harmonizing standards across Europe. ETR is publicly available at www.eurospe.org/education/education-training-syllabus and at https://www.uems.eu/&#95;&#95;data/assets/pdf&#95;file/0007/133990/UEMS-2021.17-European-Training-Requirement-in-Paediatric-Endocrinology.pdf., (© 2021 The Author(s). Published by S. Karger AG, Basel.)