LMS-based continuous pediatric reference values for soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) in the HARP cohort.

Soluble RANKL (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation, but adequate pediatric reference values are lacking. Here we provide LMS (Lambda-Mu-Sigma)-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that will allow calculation of standardized patient z-scores to assess bone modeling in children. PURPOSE: Soluble receptor activator of nuclear factor kappa B ligand (sRANKL) and osteoprotegerin (OPG) are regulators of osteoclast differentiation and activation and thus bone metabolic turnover in children. Adequate pediatric reference values for their serum/plasma concentrations are lacking. The development of Lambda-Mu-Sigma (LMS)-based continuous reference percentiles for laboratory parameters allow improved data interpretation in clinical practice. METHODS: A total of 300 children aged 0.1-18 years (166 boys) were enrolled in the HAnnover Reference values for Pediatrics (HARP) study. sRANKL and OPG were assessed by ELISA. LMS-based continuous reference percentiles were generated using RefCurv software. RESULTS: LMS-based percentiles were established for sRANKL, OPG and sRANKL/OPG ratio, which were all found to be age-dependent. sRANKL and sRANKL/OPG associated with sex. In boys, sRANKL percentiles were highest during infancy, followed by a continuous decline until the age of 7 years and a second peak around age 12-13 years. In girls, a continuous, slow decline of sRANKL percentiles was noticed from infancy onwards until the age of 13 years, followed by a rapid decline until adulthood. OPG percentiles continuously declined from infancy to adulthood. The percentiles for sRANKL/OPG ratio paralleled those of sRANKL. Serum concentrations of sRANKL correlated with OPG and serum phosphate z-scores, while OPG concentrations inversely associated with standardized body weight, BMI, and urinary phosphate to creatinine ratio (each p < 0.05). CONCLUSION: This is the first report of LMS-based continuous pediatric reference percentiles for sRANKL, OPG and sRANKL/OPG ratio that allows calculation of standardized patient z-scores to assess bone metabolic turnover in children.

LMS-Based Pediatric Reference Values for Parameters of Phosphate Homeostasis in the HARP Cohort.

CONTEXT: The assessment of phosphate homeostasis in children is challenging due to the marked changes in laboratory parameters during growth and development, and the lack of adequate reference values. OBJECTIVE: To develop Lambda-Mu-Sigma (LMS)-based continuous pediatric reference percentiles for 7 key laboratory parameters of phosphate homeostasis. METHODS: This cross-sectional, single-center study, the HAnnover Reference values for Pediatrics (HARP) study, included 455 children aged 0.1-18 years (254 boys) from outpatient hospital clinics and a secondary school program. Main outcome measures were LMS-based continuous reference percentiles for serum phosphate, plasma intact fibroblast growth factor 23 (iFGF23), and its cofactor soluble Klotho (sKlotho), tubular maximum phosphate reabsorption per glomerular filtration rate (TmP/GFR), fractional tubular reabsorption of phosphate (TRP), and urinary calcium/creatinine (Ca/Crea) and phosphate/creatinine (Pi/Crea) ratios. RESULTS: LMS-based percentiles and z-scores were established for 7 key laboratory parameters of phosphate homeostasis, which were all found to be age-dependent. Serum phosphate, TmP/GFR, and sKlotho associated with sex. Serum phosphate, TmP/GFR, and urinary Ca/Crea and Pi/Crea levels were highest in infancy and declined until age 18 years, while phosphate and TmP/GFR values reached adult levels earlier in girls compared to boys. iFGF23 concentrations are highest in infancy and fall to a stable plateau by 4 years of age, while sKlotho peaks during adolescence. CONCLUSION: This is the first report of LMS-based continuous pediatric reference percentiles for key laboratory parameters of phosphate homeostasis that allow calculation of standardized patient z-scores to facilitate test result interpretation in children and adolescents.

The Treatment of Growth Disorders in Childhood and Adolescence.

BACKGROUND: 3% of all children are unusually short, and 3% are unusually tall. New approaches have broadened the range of therapeutic options in treating growth disorders. METHODS: This review is based on publications retrieved by a selective review of the literature and on the authors' clinical experience. RESULTS: Pituitary growth hormone deficiency is treated with recombinant growth hormone. Long-acting preparations of this type became available recently, but their long-term safety and efficacy are still unknown. Vosoritide, a CNP analogue, has also been approved for the treatment of achondroplasia, and severe primary deficiency of insulin-like growth factor 1 (IGF-1) can be treated with recombinant IGF-1. In the treatment of excessively tall stature, new information on the safety of growth-attenuating treatment and an altered perception of above-average height in society have led to a change in management. CONCLUSION: There are new options for the treatment of rare causes of short stature, while new information on the safety of treatment strategies for excessive tallness have led to a reconsideration of surgical intervention. There is insufficient evidence on the benefits and risks of supraphysiological GH therapy and of newer treatment options for which there are as yet no robust data on adult height. Therefore, before any treatment is provided, physicians should give patients and their families detailed information and discuss their expectations from treatment and the goals that treatment can be expected to achieve.

Once-weekly TransCon CNP (navepegritide) in children with achondroplasia (ACcomplisH): a phase 2, multicentre, randomised, double-blind, placebo-controlled, dose-escalation trial.

Background: TransCon CNP (navepegritide) is an investigational prodrug of C-type natriuretic peptide (CNP) designed to allow for continuous CNP exposure with once-weekly dosing. This 52-week phase 2 (ACcomplisH) trial assessed the safety and efficacy of TransCon CNP in children with achondroplasia. Methods: ACcomplisH is a global, randomised, double-blind, placebo-controlled, dose-escalation trial. Study participants were recruited between June 10, 2020, and September 24, 2021. Eligible participants were prepubertal, aged 2-10 years, with genetically confirmed achondroplasia, and randomised 3:1 to once-weekly subcutaneous injections of TransCon CNP (6, 20, 50, or 100 µg CNP/kg/week) or placebo for 52 weeks. Primary objectives were safety and annualised growth velocity (AGV). ACcomplisH is registered with ClinicalTrials.gov (NCT04085523) and Eudra (CT 2019-002754-22). Findings: Forty-two participants received TransCon CNP at doses of 6 µg (n = 10; 7 female), 20 µg (n = 11; 3 female), 50 µg (n = 10; 3 female), or 100 µg (n = 11; 6 female) CNP/kg/week, with 15 receiving placebo (5 female). Treatment-emergent adverse events (TEAEs) were mild or moderate with no grade 3/4 events reported. There were 2 serious TEAEs that were assessed as not related to TransCon CNP. Eleven injection site reactions occurred in 8 participants receiving TransCon CNP and no symptomatic hypotension occurred. TransCon CNP demonstrated a dose-dependent improvement in AGV. At 52 weeks, TransCon CNP 100 µg CNP/kg/week significantly improved AGV vs placebo (least squares mean [95% CI] 5.42 [4.74-6.11] vs 4.35 [3.75-4.94] cm/year; p = 0.0218), and improved achondroplasia-specific height SDS from baseline (least squares mean [95% CI] 0.22 [0.02-0·41] vs -0·08 [-0.25 to 0.10]; p = 0.0283). All participants completed the randomised period and continued in the ongoing open-label extension period receiving TransCon CNP 100 µg CNP/kg/week. Interpretation: This phase 2 trial suggests that TransCon CNP is effective, safe, with low injection site reaction frequency, and may provide a novel, once-weekly treatment option for children with achondroplasia. These results support TransCon CNP at 100 µg CNP/kg/week in the ongoing pivotal trial. Funding: Ascendis Pharma, A/S.

The International X-Linked Hypophosphatemia (XLH) Registry: first interim analysis of baseline demographic, genetic and clinical data.

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare, hereditary, progressive, renal phosphate-wasting disorder characterized by a pathological increase in FGF23 concentration and activity. Due to its rarity, diagnosis may be delayed, which can adversely affect outcomes. As a chronic disease resulting in progressive accumulation of musculoskeletal manifestations, it is important to understand the natural history of XLH over the patient's lifetime and the impact of drug treatments and other interventions. This multicentre, international patient registry (International XLH Registry) was established to address the paucity of these data. Here we present the findings of the first interim analysis of the registry. RESULTS: The International XLH Registry was initiated in August 2017 and includes participants of all ages diagnosed with XLH, regardless of their treatment and management. At the database lock for this first interim analysis (29 March 2021), 579 participants had entered the registry before 30 November 2020 and are included in the analysis (360 children [62.2%], 217 adults [37.5%] and 2 whose ages were not recorded [0.3%]; 64.2% were female). Family history data were available for 319/345 (92.5%) children and 145/187 (77.5%) adults; 62.1% had biological parents affected by XLH. Genetic testing data were available for 341 (94.7%) children and 203 (93.5%) adults; 370/546 (67.8%) had genetic test results; 331/370 (89.5%) had a confirmed PHEX mutation. A notably longer time to diagnosis was observed in adults ≥ 50 years of age (mean [median] duration 9.4 [2.0] years) versus all adults (3.7 [0.1] years) and children (1.0 [0.2] years). Participants presented with normal weight, shorter length or height and elevated body mass index (approximately - 2 and + 2 Z-scores, respectively) versus the general population. Clinical histories were collected for 349 participants (239 children and 110 adults). General data trends for prevalence of bone, dental, renal and joint conditions in all participants were aligned with expectations for a typical population of people with XLH. CONCLUSION: The data collected within the International XLH Registry, the largest XLH registry to date, provide substantial information to address the paucity of natural history data, starting with demographic, family history, genetic testing, diagnosis, auxology and baseline data on clinical presentation.

Investigating significant health trends in growth hormone treatments registry: rationale, aims and design of a nationwide prospective registry (study protocol).

BACKGROUND: Somatropin treatment is indicated in a variety of disorders including growth hormone (GH) deficiency, Prader-Willi and Turner syndrome, chronic renal insufficiency and others. To date, almost all studies have been limited to single GH products, and no independent registry across indications and somatropin products was ever established. AIM: The present investigator-initiated registry named INSIGHTS-GHT aims to provide comprehensive information on various aspects of somatropin treatment in Germany in approved indications within routine clinical practice: drug utilization, effectiveness (including real final height, body composition), tolerability, quality of life, other patient related outcomes (PRO), and health economic variables. METHODS: Registry (prospective observational study) in specialised pediatric and adult endocrinology centres in Germany. Patients of any age are eligible for documentation, if they are on ongoing or newly initiated treatment with any approved somatropin or somatropin-related product within the labelling, available for long term follow-up documentation, and if they provided informed consent. Subjects may switch, discontinue/interrupt or initiate somatropin products at any time. They are followed up for at least 3 years (minimal study duration). Documentation is planned once or twice per year to record somatropin utilisation (product, dosing), other medications, laboratory status (glucose, lipids, GH function including stimulation tests, IGF-I, IGFBP3), if applicable, pubertal development, auxological parameters, body composition and bone age. Patient reported outcome (PRO) measures include, but are not limited to, Short Form 12 in adults and adolescents aged 14 years and over. Safety reporting includes adverse events. CONCLUSIONS: The registry documents children and adults in one joint registry, includes, at present, patients in Germany and allows documentation of patients on all approved somatropin and other growth hormone preparations. It will allow to describe the transition of subjects from adolescence to adulthood (treatment and height), to describe switches between somatotropin preparations, to perform responder analyses, and to analyse differences and similarities of somatropin utilization (by age group, sex, setting, and PRO instrument). INSIGHTS-GHT offers a broad, comprehensive research platform to assess multiple relevant aspects of somatropin treatment and outcomes (including the transition of subjects from adolescence to adulthood), allows the documentation of all GH products including long-acting GH preparations after their introduction, and will evaluate the data independently of funders. Trial registration BfArM Nr. NIS7492, DRKS registry DRKS00027394.

National survey of referrals for precocious puberty in Germany.

An unusual high number of girls were referred to our paediatric endocrine clinic with suspected precocious puberty (PP) since the beginning of the COVID-19 pandemic. We analysed our data and initiated a survey among German paediatric endocrinologists.At our centre, less than 10 patients were diagnosed of PP annually between 2015 and 2019. This increased to n=23 (2020) and n=30 (2021). A German survey confirmed this observation: Out of 44 centres which completed the questionnaire, 30/44 (68%) reported an increase of PP. Above this, 32/44 (72%) stated an increase in girls diagnosed with 'early normal puberty' since the beginning of the COVID-19 pandemic.

Effects of Burosumab Treatment on Mineral Metabolism in Children and Adolescents With X-linked Hypophosphatemia.

CONTEXT: Burosumab has been approved for the treatment of children and adults with X-linked hypophosphatemia (XLH). Real-world data and evidence for its efficacy in adolescents are lacking. OBJECTIVE: To assess the effects of 12 months of burosumab treatment on mineral metabolism in children (aged <12 years) and adolescents (aged 12-18 years) with XLH. DESIGN: Prospective national registry. SETTING: Hospital clinics. PATIENTS: A total of 93 patients with XLH (65 children, 28 adolescents). MAIN OUTCOME MEASURES: Z scores for serum phosphate, alkaline phosphatase (ALP), and renal tubular reabsorption of phosphate per glomerular filtration rate (TmP/GFR) at 12 months. RESULTS: At baseline, patients showed hypophosphatemia (-4.4 SD), reduced TmP/GFR (-6.5 SD), and elevated ALP (2.7 SD, each P < .001 vs healthy children) irrespective of age, suggesting active rickets despite prior therapy with oral phosphate and active vitamin D in 88% of patients. Burosumab treatment resulted in comparable increases in serum phosphate and TmP/GFR in children and adolescents with XLH and a steady decline in serum ALP (each P < .001 vs baseline). At 12 months, serum phosphate, TmP/GFR, and ALP levels were within the age-related normal range in approximately 42%, 27%, and 80% of patients in both groups, respectively, with a lower, weight-based final burosumab dose in adolescents compared with children (0.72 vs 1.06 mg/kg, P < .01). CONCLUSIONS: In this real-world setting, 12 months of burosumab treatment was equally effective in normalizing serum ALP in adolescents and children, despite persistent mild hypophosphatemia in one-half of patients, suggesting that complete normalization of serum phosphate is not mandatory for substantial improvement of rickets in these patients. Adolescents appear to require lower weight-based burosumab dosage than children.

Post-authorisation safety study of burosumab use in paediatric, adolescent and adult patients with X-linked hypophosphataemia: rationale and description.

Background: X-linked hypophosphataemia (XLH) is a rare, inherited, phosphate-wasting disorder that elevates fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D (1,25(OH)2D) synthesis. Disease characteristics include rickets, osteomalacia, odontomalacia, and short stature. Historically, treatment has been oral phosphate and 1,25(OH)2D supplements. However, these treatments do not correct the primary pathogenic mechanism or treat all symptoms and can be associated with adverse effects. Burosumab is a recombinant human immunoglobulin G1 monoclonal antibody against FGF23, approved for treating XLH in several geographical regions, including Europe and Israel. Burosumab restores normal serum phosphate levels, minimising the clinical consequences of XLH. Safety data on long-term treatment with burosumab are lacking owing to the rarity of XLH. This post-authorisation safety study (PASS) aims to evaluate the safety outcomes in patients aged >1 year. Methods: The PASS is a 10-year retrospective and prospective cohort study utilising data from the International XLH Registry (NCT03193476), which includes standard diagnostic and monitoring practice data at participating centres. The PASS aims to evaluate frequency and severity of safety outcomes, frequency and outcomes of pregnancies in female patients, and safety outcomes in patients with mild to moderate kidney disease at baseline, in children, adolescents and adults treated with burosumab for XLH. It is expected that there will be at least 400 patients who will be administered burosumab. Results: Data collection started on 24 April 2019. The expected date of the final study report is 31 December 2028, with two interim reports. Conclusion: This PASS will provide data on the long-term safety of burosumab treatment for XLH patients and describe safety outcomes for patients receiving burosumab contrasted with those patients receiving other XLH treatments, to help inform the future management of XLH patients. The PASS will be the largest real-world safety study of burosumab. Registry identification: The International XLH Registry is registered with clinicaltrials.gov as NCT03193476 (https://clinicaltrials.gov/ct2/show/NCT03193476), and the PASS is registered with the European Union electronic Register of Post-Authorisation Studies as EUPAS32190 (http://www.encepp.eu/encepp/viewResource.htm?id=32191).

Rickets guidance: part II-management.

Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D3, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D3 levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.

Burosumab for X-linked hypophosphatemia in children and adolescents: Opinion based on early experience in seven European countries.

Given the relatively recent introduction of burosumab in the management of X-linked hypophosphatemia (XLH), there is limited real-world data to guide its use in clinical practice. As a group of European physicians experienced with burosumab treatment in clinical practice, we convened with the objective of sharing these practice-based insights on the use of burosumab in children and adolescents with XLH. We attended two virtual meetings, then discussed key questions via Within3, a virtual online platform. Points of discussion related to patient selection criteria, burosumab starting dose, dose titration and treatment monitoring. Our discussions revealed that criteria for selecting children with XLH varied across Europe from all children above 1 year to only children with overt rickets despite conventional treatment being eligible. We initiated burosumab dosing according to guidance in the Summary of Product Characteristics, an international consensus statement from 2019 and local country guidelines. Dose titration was primarily guided by serum phosphate levels, with some centers also using the ratio of tubular maximum reabsorption of phosphate to glomerular filtration rate (TmP/GFR). We monitored response to burosumab treatment clinically (growth, deformities, bone pain and physical functioning), radiologically (rickets and deformities) and biochemically (serum phosphate, alkaline phosphatase, 1,25-dihydroxyvitamin D, 25-hydroxyvitamin D, urine calcium-creatinine ratio and TmP/GFR). Key suggestions made by our group were initiation of burosumab treatment in children as early as possible, from the age of 1 year, particularly in those with profound rickets, and a need for clinical studies on continuation of burosumab throughout adolescence and into adulthood.

Rickets guidance: part I-diagnostic workup.

Rickets is a disease of the growing child arising from alterations in calcium and phosphate homeostasis resulting in impaired apoptosis of hypertrophic chondrocytes in the growth plate. Its symptoms depend on the patients' age, duration of disease, and underlying disorder. Common features include thickened wrists and ankles due to widened metaphyses, growth failure, bone pain, muscle weakness, waddling gait, and leg bowing. Affected infants often show delayed closure of the fontanelles, frontal bossing, and craniotabes. The diagnosis of rickets is based on the presence of these typical clinical symptoms and radiological findings on X-rays of the wrist or knee, showing metaphyseal fraying and widening of growth plates, in conjunction with elevated serum levels of alkaline phosphatase. Nutritional rickets due to vitamin D deficiency and/or dietary calcium deficiency is the most common cause of rickets. Currently, more than 20 acquired or hereditary causes of rickets are known. The latter are due to mutations in genes involved in vitamin D metabolism or action, renal phosphate reabsorption, or synthesis, or degradation of the phosphaturic hormone fibroblast growth factor 23 (FGF23). There is a substantial overlap in the clinical features between the various entities, requiring a thorough workup using biochemical analyses and, if necessary, genetic tests. Part I of this review focuses on the etiology, pathophysiology and clinical findings of rickets followed by the presentation of a diagnostic approach for correct diagnosis. Part II focuses on the management of rickets, including new therapeutic approaches based on recent clinical practice guidelines.

Severe Acquired Primary Hypothyroidism in Children and its Influence on Growth: A Retrospective Analysis of 43 Cases.

INTRODUCTION: Severe acquired hypothyroidism in childhood is a rare condition, mostly caused by autoimmune thyroiditis. Scarce and inconsistent data based on small patient numbers exist concerning its impact on growth in height. METHODS: Patient files at a single centre university hospital over 8 years were retrospectively reviewed. We identified 43 patients (mean age 10.6 years, 3.3-15.25, 59% prepubertal, 88% females) in a cohort of children older than 3 years with an initial TSH>30 mIU/l and reduced T4 or fT4; congenital and drug-induced hypothyroidism were excluded. RESULTS: All patients had signs of autoimmune thyroiditis (93% positive autoantibodies, 95% typical ultrasonography, 63% goiter). Median TSH was 100 mIU/l [0.3-4 mIU/l]), median fT4 3.55 pg/ml [8-19 pg/ml], median T4 2.85 µg/dl [5.3-11 µg/dl]. Presenting symptoms included goiter (26%), tiredness (23%), weight gain (19%), and growth retardation (19%). The diagnosis was made incidentally in 26% patients. In 75% growth was retarded (median height standard deviation score (SDS)-0.55), in 17% height SDS was<-2 at diagnosis. Midparental height SDS at diagnosis correlated significantly with T4 and fT4 (r=0.77, p=0.0012 and r=0.53, p=0.021 respectively). Catch-up growth under T4 substitution was significantly greater in prepubertal than in pubertal children (p 0.049). CONCLUSION: This so far largest pediatric cohort with severe acquired hypothyroidism confirms a serious impact on growth which, however in most cases, showed a certain catch-up growth after adequate L-thyroxine therapy. The pubertal state seems to be important for catch-up growth. A significant number of patients were not diagnosed clinically, although affected by severe hypothyroidism.

Bone Fractures in Children and Young Adults With Type 1 Diabetes: Age Distribution, Fracture Location, and the Role of Glycemic Control.

Type 1 diabetes (T1D) is a known risk factor for fractures, but the underlying pathophysiology is still not fully understood. This study aims to define age peaks and frequent fracture sites of children and young adults with T1D. Additionally, associations of fractures with metabolic and lifestyle factors as well as with additional complications in individuals with T1D were analyzed. A total of 750 individuals with T1D aged ≤25 years with fractures were matched to 3750 patients with T1D without fractures by demographics and insulin regimen. Hemoglobin A1c (HbA1c) values were compared using linear regression, and logistic regression was used to calculate odds ratios (OR) for fractures in individuals with acute complications and diseases. Median (Q1-Q3) age was 12.7 (9.9 to 14.9) years in individuals with fractures and 16.3 (12.6 to 17.8) years in the entire control group with 65% versus 53% males. Peak age for fractures was 7 to <15 years in males and 9 to <11 years in females, which is earlier than reported for the general population. HbA1c (%) was significantly higher in individuals with fractures than in controls (difference of estimated means: 0.26%; 95% confidence interval [CI] 0.07-0.46), especially in postpubertal females (0.68; 0.10-1.26). Significantly higher odds for fractures were observed in individuals with severe hypoglycemia (OR = 1.90; 95% CI 1.47-2.47), especially in prepubertal females (OR = 2.81; 1.21-6.52]) and postpubertal males (2.44; 1.11-5.38), celiac disease (2.02; 1.67-2.45), and with a history of smoking (1.38; 1.02-1.88). The age peak of fractures seems to be earlier in T1D than in the general population. Poor glycemic control is related to fractures, even before puberty. Associations of HbA1c and severe hypoglycemia with fractures highly depend on age and sex. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Ectopic Calcification and Hypophosphatemic Rickets: Natural History of ENPP1 and ABCC6 Deficiencies.

Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Mild COVID-19 despite autoantibodies against type I IFNs in autoimmune polyendocrine syndrome type 1.

Autoantibodies against IFN-α and IFN-ω (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-α and IFN-ω are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-α and IFN-ω. The ability of the patients' sera to block recombinant human IFN-α and IFN-ω was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-α and IFN-ω who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females and younger than 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete.

Effectiveness and Overall Safety of NutropinAq® for Growth Hormone Deficiency and Other Paediatric Growth Hormone Disorders: Completion of the International Cooperative Growth Study, NutropinAq® European Registry (iNCGS).

Objective: The International Cooperative Growth Study, NutropinAq® European Registry (iNCGS) (NCT00455728) monitored long-term safety and effectiveness of recombinant human growth hormone (rhGH; NutropinAq® [somatropin]) in paediatric growth disorders. Methods: Open-label, non-interventional, post-marketing surveillance study recruiting children with growth disorders. Endpoints included gain in height standard deviation score (SDS), adult height, and occurrence of adverse events (AEs). Results: 2792 patients were enrolled. 2082 patients (74.6%) had growth hormone deficiency (GHD), which was isolated idiopathic in 1825 patients (87.7%). Non-GHD diagnoses included Turner syndrome (TS) (n=199), chronic renal insufficiency (CRI) (n=10), other non-GHD (n=498), and missing data for three participants. Improvements from baseline height SDS occurred at all time points to Month 132, and in all subgroups by disease aetiology. At Month 12, mean (95% CI) change in height SDS by aetiology was: idiopathic GHD 0.63 (0.61;0.66), organic GHD 0.71 (0.62;0.80), TS 0.59 (0.53; 0.65), CRI 0.54 (-0.49;1.56), and other non-GHD 0.64 (0.59;0.69). Mean height ( ± SD) at the last visit among the 235 patients with adult or near-adult height recorded was 154.0 cm ( ± 8.0) for girls and 166.7 cm ( ± 8.0) for boys. The most frequent biological and clinical non-serious drug-related AEs were increased insulin-like growth factor concentrations (314 events) and injection site haematoma (99 events). Serious AEs related to rhGH according to investigators were reported (n=30); the most frequent were scoliosis (4 events), epiphysiolysis (3 events), and strabismus (2 events). Conclusions: There was an improvement in mean height SDS in all aetiology subgroups after rhGH treatment. No new safety concerns were identified.

A Novel GNAS Duplication Associated With Loss-of-Methylation Restricted to Exon A/B Causes Pseudohypoparathyroidism Type Ib (PHP1B).

Pseudohypoparathyroidism type Ib (PHP1B) is characterized by resistance to parathyroid hormone (PTH) leading to hypocalcemia and hyperphosphatemia, and in some cases resistance toward additional hormones. Patients affected by this disorder all share a loss-of-methylation (LOM) at the differentially methylated GNAS exon A/B, which reduces expression of the stimulatory G protein α-subunit (Gsα) from the maternal allele. This leads in the proximal renal tubules, where the paternal GNAS allele does not contribute much to expression of this signaling protein, to little or no Gsα expression thereby causing PTH resistance. We now describe a PHP1B patient with a de novo genomic GNAS duplication of approximately 88 kb, which is associated with LOM restricted to exon A/B alone. Multiplex ligation-dependent probe amplification (MLPA), comparative genomic hybridization (CGH), and whole-genome sequencing (WGS) established that the duplicated DNA fragment extends from GNAS exon AS1 (telomeric breakpoint) to a small region between two imperfect repeats just upstream of LOC105372695 (centromeric breakpoint). Our novel duplication is considerably shorter than previously described duplications/triplications in that portion of chromosome 20q13 and it does not affect methylation at exons AS and XL. Based on these and previous findings, it appears plausible that the identified genomic abnormality disrupts in cis the actions of a transcript that is required for establishing or maintaining exon A/B methylation. Our findings extend the molecular causes of PHP1B and provide additional insights into structural GNAS features that are required for maintaining maternal Gsα expression and for preventing PTH-resistance. © 2020 American Society for Bone and Mineral Research (ASBMR).

Evolving pituitary hormone deficits in primarily isolated GHD: a review and experts' consensus.

Isolated growth hormone deficiency (GHD) is defined by growth failure in combination with retarded bone age, low serum insulin-like growth factor-1, and insufficient GH peaks in two independent GH stimulation tests. Congenital GHD can present at any age and can be associated with significant malformations of the pituitary-hypothalamic region or the midline of the brain. In rare instances, genetic analysis reveals germline mutations of transcription factors involved in embryogenesis of the pituitary gland and the hypothalamus. Acquired GHD is caused by radiation, inflammation, or tumor growth. In contrast to organic GHD, idiopathic forms are more frequent and remain unexplained.There is a risk of progression from isolated GHD to combined pituitary hormone deficiency (> 5% for the total group), which is clearly increased in children with organic GHD, especially with significant malformation of the pituitary gland. Therefore, it is prudent to exclude additional pituitary hormone deficiencies in the follow-up of children with isolated GHD by clinical and radiological observations and endocrine baseline tests. In contrast to primary disorders of endocrine glands, secondary deficiency is frequently milder in its clinical manifestation. The pituitary hormone deficiencies can develop over time from mild insufficiency to severe deficiency. This review summarizes the current knowledge on diagnostics and therapy of additional pituitary hormone deficits occurring during rhGH treatment in children initially diagnosed with isolated GHD. Although risk factors are known, there are no absolute criteria enabling exclusion of children without any risk of progress to combined pituitary hormone deficiency. Lifelong monitoring of the endocrine function of the pituitary gland is recommended in humans with organic GHD. This paper is the essence of a workshop of pediatric endocrinologists who screened the literature for evidence with respect to evolving pituitary deficits in initially isolated GHD, their diagnosis and treatment.

The international X-linked hypophosphataemia (XLH) registry (NCT03193476): rationale for and description of an international, observational study.

BACKGROUND: X-linked hypophosphataemia (XLH) is a rare, hereditary, progressive and lifelong phosphate wasting disorder characterised by pathological elevations in fibroblast growth factor (FGF) 23 concentration and activity; XLH has an incidence of approximately 1 in 20-25,000 individuals. Excess FGF23 activity leads to increased phosphate excretion in the kidneys - mediated by downregulation of renal tubular phosphate transporters - and reduced phosphate absorption in the intestines - due to impaired vitamin D activation. This results in impaired bone growth and mineralisation, short and disproportionate stature, leg bowing, musculoskeletal pain, spontaneous dental abscesses, rickets, and osteomalacia. The spectrum of manifestations differs between paediatric and adult patients. Those involved in the treatment of this condition face many challenges, including a lack of robust natural history and demographic data. This multicentre, international, rare-disease patient registry (XLH Registry) was established to address the paucity of data in XLH and to help inform future clinical practice. RESULTS: The XLH Registry collects standard diagnostic and monitoring practice data, including (where applicable) diagnosis and disease progression history, treatment regimens and family history; the protocol does not mandate any interventions or clinical assessments. The XLH Registry aims to recruit 1200 paediatric and adult patients with XLH over 10 years, and several data analyses and peer-reviewed publications are expected to be generated throughout this period. A post-authorisation safety study for Bburosumab, for which the registry Sponsor is the marketing authorisation holder, will be nested as a sub-study within the XLH Registry via a subsequent protocol amendment. CONCLUSION: The data collected within this rare-disease patient registry will be utilised to synthesise real-world evidence to inform the management of XLH, to improve the quality of life and standard of care of patients living with this rare debilitating disease.