OBJECTIVES:Rathke cleft cysts (RCC) in childhood are rare, often asymptomatic, and thus discovered incidentally. We aimed to summarize clinical features and pituitary function of patients with symptomatic RCC. METHODS:This retrospective study included 14 patients (8 male) from the university hospital's database (period 2005-2023). RESULTS:RCC diagnosis based on magnetic resonance imaging at 12.2 (1.8-17.6) years. Presenting symptoms were headaches (n=8), occurring alone (n=1) or with nausea/fatigue (n=2), polydipsia (n=2), or dizziness (n=3), followed by growth retardation (n=5), occurring alone (n=4) or with polydipsia (n=1). Two patients exhibited visual disturbances. Endocrinological evaluation revealed pituitary insufficiency in 10, including isolated or combined growth hormone (GH) deficiency (n=5), arginine-vasopressin deficiency (AVP-D; n=5), central hypothyroidism (n=2), and hypocortisolism (n=2). Three patients had hyperprolactinemia. Nine patients were monitored by regular imaging; five underwent surgery. In the observation group, cyst size remained unchanged in seven and decreased in two patients, while it increased in four patients treated surgically. At last presentation after 6.4 (0.33-14.8) years of follow-up, the endocrine status of the conservatively followed patients was normal in n=6, and pathological in n=3. Pituitary function did not normalize after surgery. Five patients developed hypogonadotropic hypogonadism, including two children who were followed conservatively. CONCLUSIONS:We found a high incidence of pituitary insufficiency among symptomatic pediatric RCC patients. Pituitary function was not closely related to cyst size or location and did not improve after surgery. Regular clinical and radiological follow-up is mandatory for both conservatively and surgically treated patients.

Burosumab is effective for treatment of rickets in children with X-linked hypophosphatemia (XLH). The effects of burosumab on markers and regulators of osteoblast and osteoclast acitivity are largely unknown. In this cross-sectional observational study, we investigated 7 key markers and regulators of osteoblast and osteoclast activity in 107 burosumab-treated children with XLH. We calculated z-scores for bone-specific alkaline phosphatase (BAP), procollagen-1-N-terminal propeptide (P1NP), carboxy-terminal telopeptide of type 1 collagen (CTX), tartrate-resistant acid phosphatase type 5b (TRAP5b), soluble receptor activator of NF-κB ligand (sRANKL), osteoprotegerin (OPG), and sclerostin. The median age at investigation and duration of burosumab treatment were 10.7 and 2.2 yr, respectively, with 18.7% of patients on primary burosumab treatment and 81.3% with prior treatment with phosphate and active vitamin D. Height and body mass index improved by approx. 0.3 z-score from baseline with burosumab treatment, and serum phosphate, 1,25-dihydroxyvitamin D, and alkaline phosphatase improved by 2 z-scores (each p < .01 versus prior burosunab), but phosphate (-1.8 z-score) and calcium (-0.65 z-score) remained reduced (each p < .001 versus age and sex specific reference values). The z-scores for osteoblast (BAP, P1NP) and osteoclast (CTX, TRAP5b) activity markers and for the osteoblast suppressor sclerostin were increased (each p < .001). Standardized sRANKL was reduced (p < .05), while the RANKL inhibitor OPG was increased resulting in a reduced sRANKL/OPG ratio (each p < .001). Multivariate analysis revealed significant associations between serum sclerostin and serum phosphate (negative), serum calcium and vitamin D sufficiency (positive), and primary burosumab treatment with BAP (negative). In this real-world setting, pediatric XLH patients receiving burosumab treatment showed persisting mild hypophosphatemia and increased markers of osteoblast and osteoclast acitivity despite negative counter-regulation of osteoblasts by sclerostin and osteoclasts by OPG/RANKL. Our data suggest a more pronounced normalization osteoblast activity when children are primarily treated with burosumab and underscore the need for adequate vitamin D supplementation.

In children and adolescents, impaired growth due to tyrosine kinase inhibitor therapy remains an insufficiently studied adverse effect. This study examines demographic, pharmacological, and genetic factors associated with impaired longitudinal growth in a uniform pediatric cohort treated with imatinib. We analyzed 94 pediatric patients with chronic myeloid leukemia (CML) diagnosed in the chronic phase and treated with imatinib for >12 months who participated in the Germany-wide CML-PAEDII study between February 2006 and February 2021. During imatinib treatment, significant height reduction occurred, with medians of -0.35 standard deviation score (SDS) at 12 months and -0.76 SDS at 24 months. Cumulative height SDS change (Δheight SDS) showed a more pronounced effect in prepubertal patients during the first year but were similar between prepubertal and pubertal subgroups by the second year (-0.55 vs. -0.50). From months 12 to 18 on imatinib, only 18% patients achieved individually longitudinal growth adequate to the growth standard (Δheight SDS≥0). When patients were divided into two subgroups based on median Δheight SDS (classifier Δheight SDS > or ≤-0.37) after one year on imatinib therapy, cohort 1 (Δheight SDS extending -0.37) showed younger age at diagnosis, a higher proportion of prepubertal children, but also better treatment response and higher imatinib serum levels. Exploring the association of growth parameters with pharmacokinetically relevant single nucleotide polymorphisms, known for affecting imatinib response, showed no correlation. This retrospective study provides new insights into imatinib-related growth impairment. We emphasize the importance of optimizing treatment strategies for pediatric patients to realize their maximum growth potential.

While subclinical or overt hypothyroidism are common in Down syndrome (DS); Graves’ disease (GD) is rare (ranges 0.6–3%). We aimed to evaluate the clinical features, course, and treatment of GD in children with DS and compare them with those without DS. Among 161 children with GD, 13 (8 female, 5 male) had DS (8%). Data were collected retrospectively from patients’ medical records. The mean age at diagnosis was 10.6 ± 4.5 years, with a female-to-male ratio 1.6:1. The main symptoms were weight loss (n = 6), increased irritability (n = 3), and increased sweating (n = 3). None had orbitopathy. Seven of 11 patients with a thyroid ultrasound at diagnosis had a goitre. On admission, all had thyroid-stimulating hormone (TSH) <0.01 mU/L (normal range (NR): 0.51–4.30), free triiodothyronine, free thyroxine (mean ± s.d.), and thyrotrophin receptor antibodies (median, range) were 22.2 ± 10.2 pmol/L (NR: 3.5–8.1), 50.2 ± 18.7 pmol/L (NR 12.6–20.9), and 17.0 (2.89–159.0) U/L (NR <1), respectively. Patients were treated either with methimazole (n = 10) or carbimazole (n = 3), a dose of 0.54 ± 0.36 mg/kg/day. The treatment was ‘block and replace’ in ten patients and ‘dose titration’ in three patients, with a mean duration of 43.4 ± 11.0 months. Of 13 patients, four are still receiving primary treatment, three are in remission, one patient had two medically treated recurrences, three underwent surgery without complications, and two patients were lost to follow-up. Our data show that the clinical course of GD in patients with DS was similar to those without DS and suggest that a prolonged medical therapy should be the preferred option.

al. (2020) Lipid profiles in Children and Adolescents with Classic Congenital Adrenal Hyperplasia due to 21-Hydroxylase Deficiency (CAH). J Hormonal Dis Endocrine Res 1: 105

During the shutdown of the CERN Large Hadron Collider in 2013-2014, an additional pixel layer was installed between the existing Pixel detector of the ATLAS experiment and a new, smaller radius beam pipe. The motivation for this new pixel layer, the Insertable B-Layer (IBL), was to maintain or improve the robustness and performance of the ATLAS tracking system, given the higher instantaneous and integrated luminosities realised following the shutdown. Because of the extreme radiation and collision rate environment, several new radiation-tolerant sensor and electronic technologies were utilised for this layer. This paper reports on the IBL construction and integration prior to its operation in the ATLAS detector.

Objective:Classic congenital adrenal hyperplasia (CAH) secondary to 21-hydroxylase deficiency is characterized by increased prenatal adrenal androgen secretion. There are a small number of reports in the literature showing higher birth weight and length in CAH newborns.Methods:We analyzed birth weight and length data of 116 German newborns (48 boys, 68 girls) with classic CAH who were born during the period from 1990 to 2017. All children have been followed or are currently treated as outpatients in our clinic. All children were born at term. The mothers were healthy and their pregnancies were uneventful. The diagnosis of CAH was confirmed by molecular analyses of the CYP21A2 gene. Birth data were calculated as standard deviation (SD) scores according to German reference values.Results:Weight and length in male CAH newborns (mean ± SD) (3601±576 g; 52.4±2.85 cm) were significantly higher than in female CAH newborns (3347±442 g; 51.2±2.55 cm), but male-female differences in the CAH cohort were lost when the data were converted into SD scores. The birth sizes of the CAH newborns did not differ from the reference group. The birth sizes also did not differ between the different CAH genotypes. Maternal age, mode of delivery and maternal parity had no influence on birth size.Conclusion:Our data show that prenatal hyperandrogenism does not affect fetal growth.

Data on adrenarche and pubarche in girls with Turner syndrome (TS) are inconsistent in the literature. The cohort consisted of 94 girls and young women with TS born between 1971 and 2001 (age range: 3.1–23.2 yrs.), who were treated with human growth hormone and regularly presented at our outpatient clinic every 4 to 6 months.The longitudinal data of all patients were ascertained retrospectively from patient charts. The data collection ended in January 2016. Adrenarche was assessed by serum DHEAS levels and pubertal status by Tanner stages. Pubarche was defined as the appearance of pubic hair (PH2), whereas spontaneous puberty was defined as Tanner stage B2. The patients were retrospectively subdivided in two groups with regard to pubertal development: group 1 (n = 21) with spontaneous puberty and group 2 (n = 70) with induced puberty. Since blood samples were not taken at every visit, we generated seven groups according to the age of the children at which the blood samples were taken: 3–5, 5–7, 7–9, 9–11, 11–13, 13–15, and 15–17 yrs. Serum DHEAS and follicle-stimulating hormone (FSH) levels were measured by chemiluminescence immunoassay and compared with those of a control group of healthy girls. Adrenarche started in TS girls between 5 and 7 years. TS girls had higher DHEAS levels than the control group, with statistically significant differences in the age groups 7 to 17 years. No differences were determined between the TS girls with spontaneous puberty and those with POI. TS girls in group 2 reached the Tanner stages PH2 (p < 0.04), PH3 (p < 0.01), PH4 and PH5 (p < 0.001) markedly later than TS girls in group 1. The onset of adrenarche in girls with TS undergoing GH therapy does not differ from that in healthy girls. However, adrenarche is more pronounced in girls with TS. There is no difference in DHEAS levels between the TS girls with spontaneous puberty and the TS girls with primary ovarian insufficiency (POI), while the tempo of pubarche is markedly slower in the girls with POI.

We report on a boy of Albanian descent with the history of juvenile myelomonocytic leukemia (JMML). JMML was diagnosed at the age of 17 months and treated by hematopoietic stem cell transplantation (HSCT). At the age of 14.3 years, about 12 years after HSCT, he was hospitalized with an adrenal crisis. Hormone findings were consistent with primary adrenal insufficiency. Autoimmune adrenalitis was confirmed by positive autoantibodies against 21-hydroxylase and adrenal tissue. Since autoimmune Hashimoto thyroiditis was already known from the age of 9 years, we assume that both diseases are part of the spectrum of autoimmune polyglandular syndrome (APS) type 2. APS type 2 is a rare endocrine disease characterized by Addison's disease along with autoimmune thyroid disease and/or type 1 diabetes.

Background The most common form of congenital adrenal hyperplasia is 21-hydroxylase deficiency (CAH). Both men and women with classic CAH have lower fertility rates than the general population, and an increased rate of miscarriages has been reported in affected women. There are no data on the incidence rate of miscarriages in families with an offspring that have classic CAH. Methods We studied families with a history of classic CAH. The families came from different parts of Germany and attended the annual meeting of the German CAH support group for parents and patients which was held in Hamburg in September 2014. The data was collected anonymously by a paper-based questionnaire which was completed by the families at home. The families also accepted the responsibility to address this question to their siblings. In all, the data of 50 families with at least one child with classic CAH, and the data of 164 parental siblings were available for evaluation. Miscarriage rates were calculated in relation to the reported pregnancies. Results Twenty-two miscarriages were reported from 19 families. At least one miscarriage occurred in 38% of the families, three families experienced two miscarriages and 16 families had one miscarriage each. The mean miscarriage rate was 15.8%. The heterozygous mothers had a total of 90 siblings (41 m, 49 f), while 74 siblings (33 m, 41 f) were reported from the heterozygous fathers. The miscarriage rate was 10.1% in the families of the mothers` siblings, and 11.4% in the families of the fathers` siblings. The genotype was known in all parents that have an offspring with classic CAH, but not defined in 82% of the maternal siblings, and in 86% of the paternal siblings. No child with classic CAH has been diagnosed in any of the sibling’s families to date. Conclusion Our data show that the miscarriage rate in German families with a child with classic CAH is not elevated.

Abstract Background: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. Methods: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. Results: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. Conclusions: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.

During the shutdown of the CERN Large Hadron Collider in 2013-2014, an additional pixel layer was installed between the existing Pixel detector of the ATLAS experiment and a new, smaller radius beam pipe. The motivation for this new pixel layer, the Insertable B-Layer (IBL), was to maintain or improve the robustness and performance of the ATLAS tracking system, given the higher instantaneous and integrated luminosities realised following the shutdown. Because of the extreme radiation and collision rate environment, several new radiation-tolerant sensor and electronic technologies were utilised for this layer. This paper reports on the IBL construction and integration prior to its operation in the ATLAS detector.

We recently showed that a 3-year growth hormone (GH) treatment improves linear growth in severely short children with X-linked hypophosphatemic rickets (XLH). It is unknown if GH therapy increases adult height in XLH patients.

The centrality dependence of the mean charged-particle multiplicity as a function of pseudorapidity is measured in approximately 1 mu b(-1) of proton-lead collisions at a nucleon-nucleon centre-of-mass energy of root s(NN) = 5.02 TeV using the ATLAS detector at the Large Hadron Collider. Charged particles with absolute pseudorapidity less than 2.7 are reconstructed using the ATLAS pixel detector. The p + Pb collision centrality is characterised by the total transverse energy measured in the Pb-going direction of the forward calorimeter. The charged-particle pseudorapidity distributions are found to vary strongly with centrality, with an increasing asymmetry between the proton-going and Pb-going directions as the collisions become more central. Three different estimations of the number of nucleons participating in the p + Pb collision have been carried out using the Glauber model as well as two Glauber-Gribov inspired extensions to the Glauber model. Charged-particle multiplicities per participant pair are found to vary differently for these three models, highlighting the importance of including colour fluctuations in nucleon-nucleon collisions in the modelling of the initial state of p + Pb collisions.

This paper describes the data acquisition and high level trigger system of the ATLAS experiment at the Large Hadron Collider at CERN, as deployed during Run 1. Data flow as well as control, configuration and monitoring aspects are addressed. An overview of the functionality of the system and of its performance is presented and design choices are discussed.