International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia - data from the I-CAH registry.

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

Gonadectomy in conditions affecting sex development: a registry-based cohort study

Objectives To determine trends in clinical practice for individuals with DSD requiring gonadectomy. Design Retrospective cohort study. Methods Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019. Results Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries. Conclusions The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy

GHD Diagnostics in Europe and the US: An Audit of National Guidelines and Practice

Introduction: Almost 20 years after the first international guidelines on the diagnosis and treatment of GHD have been published, clinical practice varies significantly. The low accuracy of endocrine tests for GHD and the burden caused by ineffective treatment of individual patients were strong motives for national endocrine societies to set up national guidelines regarding how to diagnose GHD in childhood. This audit aims to review the current state and identify common changes, which may improve the diagnostic procedure. Methods: A group of eight German pediatric endocrinologists contacted eight pediatric endocrinologists from Spain, France, Poland, the UK, the Netherlands, Denmark, Italy, and the US. Each colleague responded as a representative for the own country to a detailed questionnaire containing 22 open questions about national rules, guidelines, and practice with respect to GHD diagnostics and GH prescription. The results were presented and discussed in a workshop and then documented in this study which was reviewed by all participants. Results: National guidelines are available in 7 of 9 countries. GH is prescribed by pediatric endocrinologists in most countries. Some countries have established boards that review and monitor prescriptions. Preferred GH stimulation tests and chosen cutoffs vary substantially. Overall, a trend to lowering the GH cutoff was identified. Priming is becoming more popular and now recommended in 5 out of 9 countries; however, with different protocols. The definition of pretest-conditions that qualify the patient to undergo GH testing varies substantially in content and strictness. The most frequently used clinical sign is low height velocity, but definition varies. Height, IGF-1, and bone age are additional parameters recommended in some countries. Conclusions: GHD diagnostics varies substantially in eight European countries and in the US. It seems appropriate to undertake further efforts to harmonize endocrine diagnostics in Europe and the US based on available scientific evidence

Steroid metabolomics: A rapid computational approach for accurate differentiation of inborn disorders of steroidogenesis

Background: Measurement of steroid metabolite excretion in urine by gas chromatography-mass spectrometry (GC-MS) provides a comprehensive profile of an individual’s adrenal and gonadal steroid production. It has long been acknowledged as a useful tool for diagnosis of inborn disorders of steroidogenesis leading to congenital adrenal hyperplasia and disorders of sex development. Ratios of steroid metabolites can be employed as surrogates for enzymatic activities of distinct steroidogenic enzymes and can also be applied to single random urine samples, making this a more feasible approach for use with paediatric patients. However, widespread use in the acute setting for diagnosis of these disorders is hampered by the considerable expertise required for interpretation. Here we developed a novel steroid metabolomics approach for the detection and differential diagnosis of inborn steroidogenic disorders, combining mass spectrometry-based steroid profiling with machine learning-based data analysis, suitable for automation and interpretation without specialist expertise. Methods: We performed multi-steroid profiling by GC-MS, quantifying 34 steroid metabolites, in urine samples from 829 healthy controls and 178 untreated patients with inborn steroidogenic disorders. This cohort included patients with inborn deficiencies in the following enzymes: CYP21A2 (n=26), CYP11B1 (n=12), CYP17A1 (n=30), POR (n=37), HSD3B2 (n=22), and SRD5A2 (n=51). We assessed the diagnostic performance of conventional biochemical assessment employing 15 steroid precursor-to-product ratios, each historically established as indicative of a distinct steroidogenesis disorder. We compared this to the performance of our novel steroid metabolomics approach, which involved analysis of the GC-MS multi-steroid profiles by a custom-designed approach, Angle Learning Vector Quantization (ALVQ), which classifies samples by comparing similarity of their steroid metabolome to representative steroid metabolome prototypes for each enzyme deficiency. Results: The conventional biochemical steroid ratio approach demonstrated acceptable sensitivity and specificity. However, the automated steroid metabolomics approach (ALVQ) performed significantly superior to this, particularly with regards to specificity. For differentiating patients from healthy controls, sensitivity and specificity of ALVQ were 97% and 98%, respectively. For differentiation of each pathogenic enzymatic defect, ALVQ performed superiorly, with sensitivity and specificity ranging between 95 and 100%. Conclusion: We present a novel steroid metabolomics approach, able to automatically detect and differentiate six different inborn disorders of steroidogenesis, with improved performance when compared to reference standard metabolite ratios. Steroid metabolomics can expedite and standardise interpretation of complex urinary steroid metabolome data, making this technique more accessible to clinicians, and has excellent potential for implementation in routine clinical practice