Whole genome sequencing in adults with clinical hallmarks of hypophosphatasia negative for ALPL variants.

BACKGROUND: Hypophosphatasia (HPP) is a rare disease caused by deficient activity of tissue-nonspecific alkaline phosphatase (ALP), encoded by the ALPL gene. The primary objective was to explore novel ALPL variants by whole genome sequencing (WGS) in patients with HPP who previously tested negative by standard methods for ALPL variants. The secondary objective was to search for genes beyond ALPL that may reduce ALP activity or contribute to HPP symptoms. METHODS AND RESULTS: WGS was performed in 16 patients clinically diagnosed with HPP who had ALP activity below the normal range and tested negative for ALPL variants. Genetic variants in ALPL and genes possibly associated with low ALP activity or phenotypic overlap with HPP were assessed. All 16 patients had ALP activity below the normal range. WGS did not identify any novel disease-causing ALPL variants. Positive findings for other gene variants were identified in 4 patients: 1 patient presented with variants in COL1A1, NLRP12, and SCN9A, coding for collagen, type, I alpha-1 chain, nod-like receptor pyrin domain containing 12, and sodium voltage-gated channel alpha subunit 9, respectively; 1 presented with a heterozygous, likely pathogenic variant in P3H1 coding for prolyl 3 hydroxylase 1; 1 presented with a heterozygous pathogenic variant in SGCE, coding for sarcoglycan epsilon; and 1 presented with a heterozygous variant of uncertain significance in VDR, encoding vitamin D receptor. CONCLUSION: Genomic analysis did not identify novel ALPL variants or a pattern of disease-causing variants in genes other than ALPL to explain the HPP phenotype in these patients. REGISTRATION: Clinicaltrials.gov identifier: NCT04925804.

New insights into the landscape of ALPL gene variants in patients with hypophosphatasia from the Global HPP Registry.

Hypophosphatasia (HPP) is a rare, inherited metabolic disease characterized by low tissue-nonspecific alkaline phosphatase activity due to ALPL gene variants. We describe ALPL variants from the observational, prospective, multinational Global HPP Registry. Inclusion in the analysis required a diagnosis of HPP, low serum ALP activity, and ≥1 ALPL variant. Of 1176 patients enrolled as of September 2022, 814 met inclusion criteria in Europe (48.9%), North America (36.7%), Japan (10.2%), Australia (2.6%), and elsewhere (1.6%). Most patients (74.7%) had 1 ALPL variant; 25.3% had ≥2 variants. Nearly all patients (95.6%) had known disease-causing variants; 4.4% had variants of uncertain significance. Disease-causing variants were predominantly missense (770/1556 alleles). The most common variants were c.571G>A (102/1628 alleles), c.1250A>G (66/1628 alleles), and c.1559del (61/1628 alleles). Variant profiles were generally consistent, except in Japan, where a higher proportion of patients (68.7%) had ≥2 ALPL variants, likely because more had disease onset before age 6 months (53.0% vs. 10.1%-23.1% elsewhere). Frameshift mutations (61/164 alleles) and inframe deletions (7/164 alleles) were more common in Japan. Twenty-three novel variants were discovered, each in a single geographic region, predominantly Europe. Analyses confirmed previously known ALPL variants, identified novel variants, and characterized geographic variation in frequency and type of ALPL variants in a large population.

Effectiveness of asfotase alfa for treatment of adults with hypophosphatasia: results from a global registry.

BACKGROUND: Hypophosphatasia (HPP) is a rare inherited disease caused by deficient activity of tissue-nonspecific alkaline phosphatase. Many adults with HPP have a high burden of disease, experiencing chronic pain, fatigue, limited mobility, and dental issues, contributing to decreased health-related quality of life (HRQoL). HPP may be treated with the enzyme replacement therapy asfotase alfa though real-world data in adults are limited. This analysis was conducted to assess the clinical effectiveness of asfotase alfa among adults in the Global HPP Registry. METHODS: The Global HPP Registry is an observational, prospective, multinational study. Adults ≥ 18 years of age were included in this analysis if they had serum alkaline phosphatase (ALP) activity below the age- and sex-adjusted reference ranges, and/or ALPL variant(s), and received asfotase alfa for ≥ 6 months. Mobility was assessed with the 6-Minute Walk Test (6MWT), and patient-reported outcomes tools were used to assess pain (Brief Pain Inventory-Short Form), quality of life (36-item Short Form Health Survey, version 2 [SF-36v2]), and disability (Health Assessment Questionnaire-Disability Index) at multiple time points from baseline through Month 36. Data were collected as per usual standard of care; patients may not have contributed data at all time points. RESULTS: A total of 190 patients met the inclusion criteria. For patients with ≥ 1 follow-up measurement, the mean distance achieved on 6MWT increased from 404 m (range 60-632 m) at baseline (n = 31) to 484 m at Month 12 (range 240-739 m; n = 18) and remained above baseline through Month 36 (n = 7). Improvements in mean self-reported pain severity scores ranged from - 0.72 (95% CI: - 1.23, - 0.21; n = 38) to - 1.13 (95% CI: - 1.76, - 0.51; n = 26) and were observed at all time points. Improvements in the Physical Component Summary score of SF-36v2 were achieved by Month 6 and sustained throughout follow-up. There was a trend toward improvement in the Mental Component Summary score of SF-36v2 at most time points, with considerable fluctuations from Months 12 (n = 28) through 36 (n = 21). The most frequent adverse events were injection site reactions. CONCLUSIONS: Adults with HPP who received asfotase alfa for ≥ 6 months experienced improvements in mobility, physical function, and HRQoL, which were maintained over 3 years of follow-up. REGISTRATION: NCT02306720; EUPAS13514.

Clinical Profiles of Children with Hypophosphatasia Prior to Treatment with Enzyme Replacement Therapy: An Observational Analysis from the Global HPP Registry.

INTRODUCTION: To better understand the clinical profiles of children with hypophosphatasia (HPP) prior to treatment with enzyme replacement therapy (ERT). METHODS: Pretreatment demographics and medical histories of ERT-treated children (aged < 18 years) enrolled in the Global HPP Registry (2015-2020) were analyzed overall, by age at first HPP manifestation (< 6 months versus 6 months to 18 years) and by geographic region (United States/Canada, Europe, and Japan). RESULTS: Data from 151 children with HPP were analyzed. Sex distribution was balanced overall (52.3% female; 47.7% male) but differed in Japan (63.0% female; 37.0% male). Prior to ERT initiation, common manifestations were skeletal (67.5%) and extraskeletal, with the foremost being muscular (48.3%), constitutional/metabolic (47.0%), and neurologic (39.7%). A high proportion of children who first presented at < 6 months of age (perinatal/infantile period) had a history of bone deformity (59.3%) and respiratory failure (38.3%), while those aged 6 months to 18 years at first manifestation had a predominance of early loss of primary teeth (62.3%) and gross motor delay (41.0%). Japan reported a younger median age overall, the highest proportion of skeletal (80.4%) manifestations and growth impairment, while European data showed the highest proportion of muscular manifestations (70.7%). In the United States/Canada, skeletal and muscular manifestations were reported at the same frequency (57.4%). DISCUSSION/CONCLUSION: Prior to ERT, skeletal and extraskeletal manifestations were commonly reported in children with HPP, with differences by age at first HPP manifestation and geographical region. Comprehensive assessments of children with HPP are warranted prior to ERT initiation.

Effects of asfotase alfa in adults with pediatric-onset hypophosphatasia over 24 months of treatment.

BACKGROUND: Hypophosphatasia (HPP) is a rare, heritable metabolic disorder caused by deficient activity of tissue-nonspecific alkaline phosphatase (TNSALP). Asfotase alfa (AA) is a human recombinant TNSALP that promotes bone mineralization and is approved to treat eligible patients with HPP. METHODS: This prospective single-center observational study evaluated AA in adults with pediatric-onset HPP over 2 years of treatment (ClinicalTrials.govNCT03418389). Primary outcomes evaluated physical function; secondary outcomes assessed quality of life (QoL) and pain. RESULTS: The study included 17 females and 5 males (mean age: 48.7 years). Median distance walked in the 6-Minute Walk Test increased significantly from baseline to 12 months (P = 0.034) and results were sustained. Median Timed Up and Go test time significantly decreased from baseline at 12 (P = 0.003) and 24 months (P = 0.005), as did the median chair rise time test at 12 (P = 0.003) and 24 months (P < 0.002). The change from baseline in usual gait speed was significant at 12 (P = 0.003) and 24 months (P = 0.015). Mean dominant and nondominant hand grip strength improved at 24 months (P = 0.029 and P = 0.019, respectively). Median Short Form 36 Physical Component Summary scores significantly improved from baseline at 12 (P = 0.012) and 24 (P = 0.005) months, and median Lower Extremity Functional Scale scores improved from baseline at 12 (P = 0.001) and 24 (P = 0.002) months. No significant change was noted in pain level at these timepoints. While injection site reactions occurred in 86.4 % of the participants, there were no severe side effects or safety findings. CONCLUSIONS: Adults with pediatric-onset HPP treated with AA experienced marked improvement in functional and QoL outcomes that were observed as early as within 3 months of initial treatment and were sustained over 24 months.

Improving care pathways for people living with rare bone diseases (RBDs): outcomes from the first RBD Summit.

INTRODUCTION: Rare bone diseases (RBDs) are a heterogenous group of disorders that are poorly understood and challenging to treat. This creates a plethora of unmet needs for people with RBDs as well as their families and care providers, including diagnostic delays, limited access to expert care, and a lack of specialized treatments. The RBD Summit, which took place across 2 days in November 2021, was a virtual meeting of 65 RBD experts from clinical, academic, and patient communities as well as the pharmaceutical industry. The first meeting of its kind, the RBD Summit aimed to facilitate dialog and information exchange between delegates to advance knowledge and awareness of RBDs and improve patient outcomes. METHODS: Key challenges were discussed, and actions for overcoming them were proposed, including how obstacles to diagnosis can be overcome by (a) improving awareness of RBDs, (b) the implementation of a person-centered care pathway, and (c) how to narrow the communication gap between patients and healthcare professionals. RESULTS: Agreed actions were categorized as short term and long term, and priorities determined. CONCLUSION: In this position paper, we provide an overview of key discussions from the RBD Summit, summarize the subsequent action plan, and discuss the next steps in this continued collaboration.

Impact of muscular symptoms and/or pain on disease characteristics, disability, and quality of life in adult patients with hypophosphatasia: A cross-sectional analysis from the Global HPP Registry.

Introduction: Hypophosphatasia (HPP) manifests in adults as fractures/pseudofractures, pain, muscle weakness, and other functional impairments. Better phenotypic disease characterization is needed to help recognize disability and treat patients with HPP. Methods: Baseline/pretreatment demographic, clinical characteristic, and patient-reported disability/health-related quality-of-life (HRQoL) data from adults (≥18 y) in the Global HPP Registry (NCT02306720) were stratified by presence of overt skeletal manifestations (skeletal group) versus muscular/pain manifestations without skeletal manifestations (muscular/pain group) and summarized descriptively. Disability was measured using the Health Assessment Questionnaire-Disability Index (HAQ-DI), and HRQoL using the 36-item Short Form Health Survey (SF-36v2). Results: Of 468 adults, 300 were classified into the skeletal group and 73 into the muscular/pain group. The skeletal group had a higher median age at baseline (50.1 vs 44.4 y; P=0.047) but a lower median age at first HPP manifestation (12.3 vs 22.1 y; P=0.0473), with more signs and symptoms (median, 4 vs 3; P<0.0001) and involved body systems (median, 3 vs 2; P<0.0001) than the muscular/pain group. More patients in the skeletal group required any use of mobility aids (22.6% vs 3.5%, respectively; P=0.001). Six-Minute Walk test distances walked were similar between groups. SF-36v2 and HAQ-DI scores were similar between groups for physical component summary (n=238; mean [SD]: 40.2 [11.0] vs 43.6 [11.2]; P=0.056), mental component summary (n=238; mean [SD]: 43.6 [11.3] vs 43.8 [11.8]; P=0.902), and HAQ-DI (n=239; median [minimum, maximum]: 0.4 [0.0, 2.7] vs 0.3 [0.0, 2.1]; P=0.22). Conclusion: Adults with HPP experience similar QoL impairment regardless of skeletal involvement. Registration: https://clinicaltrials.gov/ct2/show/NCT02306720 and https://www.encepp.eu/encepp/viewResource.htm?id=47907, identifier NCT02306720; EUPAS13514.

Growth and disease burden in children with hypophosphatasia.

Objective: Hypophosphatasia, an inborn error of metabolism characterized by impaired bone mineralization, can affect growth. This study evaluated relationships between anthropometric parameters (height, weight, and body mass index) and clinical manifestations of hypophosphatasia in children. Design: Data from children (aged <18 years) with hypophosphatasia were analyzed from the observational Global Hypophosphatasia Registry. Methods: Anthropometric parameters were evaluated by age group (<2 years and ≥2 years) at assessment. The frequency of hypophosphatasia manifestations was compared between children with short stature (< percentile) and those with normal stature. Results: This analysis included 215 children (54.4% girls). Short stature presented in 16.1% of children aged <2 years and 20.4% of those aged ≥2 years at assessment. Among those with available data (n = 62), height was below the target height (mean: -0.66 standard deviations). Substantial worsening of growth (mean delta height z score: -1.45; delta weight z score: -0.68) occurred before 2 years of age, while in those aged ≥2 years, anthropometric trajectories were maintained (delta height z score: 0.08; delta weight z score: 0.13). Broad-ranging hypophosphatasia manifestations (beyond dental) were observed in most children. Conclusions: Short stature was not a consistent characteristic of children with hypophosphatasia, but growth impairment was observed in those aged <2 years, indicating that hypophosphatasia might affect growth plate activity during infancy. In addition, a broad range of clinical manifestations occurred in those above and below the third percentile for height, suggesting that height alone may not accurately reflect hypophosphatasia disease burden and that weight is less affected than longitudinal growth.

Clinical profiles of treated and untreated adults with hypophosphatasia in the Global HPP Registry.

BACKGROUND: The clinical signs and symptoms of hypophosphatasia (HPP) can manifest during any stage of life. The age at which a patient's symptoms are reported can impact access to targeted treatment with enzyme replacement therapy (asfotase alfa), as this treatment is indicated for patients with pediatric-onset HPP in most countries. As such, many patients reported to have adult-onset HPP typically do not receive treatment. Comparison of the disease in treated and untreated adult patients is confounded by the approved indication. To avoid this confounding factor, a comparison between baseline disease manifestations prominent among treated versus untreated adult patients was limited to those with pediatric-onset HPP using data collected from the Global HPP Registry. The hypothesis was that treated adults will have a greater disease burden at baseline than untreated adults. The analysis of disease manifestations in adults with adult-onset HPP was conducted separately. RESULTS: A total of 398 adults with HPP were included; 213 with pediatric-onset (114 treated, 99 untreated) and 141 with adult-onset HPP (2 treated and 139 untreated). The treated, pediatric-onset patients were more likely to have a history of pain (prevalence ratio [PR]: 1.3, 95% confidence interval [CI] 1.1, 1.4), skeletal (PR: 1.3, 95% CI 1.1, 1.6), constitutional/metabolic (PR: 1.7, 95% CI 1.3, 2.0), muscular (PR: 1.8, 95% CI 1.4, 2.1) and neurological (PR: 1.7, 95% CI 1.1, 2.3) manifestations of HPP, and also had poorer measures for health-related quality of life, pain, and disability compared with untreated pediatric-onset patients. In patients with adult-onset HPP, the most frequent signs and symptoms were chronic bone pain (52.5%), dental manifestations (42.6%), fatigue (23.4%), recurrent fractures or pseudofractures (22.0%), and generalized body pain (22.0%). CONCLUSIONS: Along with the more classical skeletal signs and symptoms, pain, muscular, and constitutional/metabolic manifestations are common in adults with HPP, regardless of age of disease onset, highlighting a full spectrum of HPP manifestations.

Severe Congenital Hypothyroidism Due to a Novel Deep Intronic Mutation in the TSH Receptor Gene Causing Intron Retention.

In 3 Somalian siblings with severe nongoitrous congenital hypothyroidism, exome sequencing identified a variant in TSHR predicted to be benign in isoform 3 but leading to an intronic mutation in isoform 1 (NM_00369:c.692 + 130C>A), which is the isoform expressed in the thyroid. This mutation creates a pseudoexon that results in a protein that, if transcribed, would lack the transmembrane domain, thereby hampering its expression at the cell surface. Our findings illustrate that the interpretation of exome analysis requires knowledge of the relevant isoform expression and of the biology of the disease. This is the first description of a deep intronic mutation creating a pseudoexon and inactivating the thyroid stimulating hormone (TSH) receptor.

Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic.

OBJECTIVES: This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range. METHODS: Data were collected from February 2016 to October 2018 for 41 patients (n = 20 in the HPP group, n = 21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging. RESULTS: Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5'-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43 IU/L or less and PLP level of 120 nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases. CONCLUSION: This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.

AN ADJUNCTIVE USE OF ASFOTASE ALFA AND ZOLEDRONIC ACID AFTER SPINAL SURGERY IN NEUROFIBROMATOSIS TYPE 1 RELATED DYSTROPHIC SCOLIOSIS.

OBJECTIVE: Dystrophic scoliosis is a serious skeletal manifestation of neurofibromatosis 1 (NF1). The condition requires surgical intervention that is frequently associated with poor outcome due to the high rate of impaired bone healing, pseudoarthrosis, and loosening of the spinal instrumentation. New therapeutic approaches are needed to improve surgical outcomes. METHODS: Clinical, laboratory, and radiographic data are presented. RESULTS: A 54-year-old woman with severe NF1 related dystrophic scoliosis and 3 prior surgical interventions underwent revision of lumbar fusion with intraoperative recombinant human bone morphogenetic protein (rhBMP-2) for loosening and a fracture of the left vertical rod at the L4 pedicle screw connection. Two days after surgery, a computed tomography (CT) scan revealed a left posterior iliac periscrew fracture. Given a high risk of mechanical failure, zoledronic acid and asfotase alfa were also administered at 3 and 7 months after surgery. At 14 months after surgery, back pain improved, and a CT scan showed stable spinal fusion and a healed left posterior iliac screw fracture. CONCLUSION: Combination therapy including asfotase alfa with rhBMP-2 and bisphosphonate resulted in solid arthrodesis after spinal surgery in NF1-related dystrophic scoliosis.

Physical Function and Health-Related Quality of Life in Adults Treated With Asfotase Alfa for Pediatric-Onset Hypophosphatasia.

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease characterized by tissue-nonspecific alkaline phosphatase deficiency resulting in musculoskeletal and systemic clinical manifestations. This observational study evaluated the effectiveness of enzyme replacement therapy with asfotase alfa on physical function and health-related quality of life (HRQoL) among adults with pediatric-onset HPP who received asfotase alfa for 12 months at a single center (ClinicalTrial.gov no.: NCT03418389). Primary outcomes evaluated physical function with the 6-minute walk test (6MWT), timed up-and-go (TUG) test, Short Physical Performance Battery (SPPB), and handheld dynamometry (HHD). Secondary outcome measures included the Lower Extremity Functional Scale (LEFS), pain prevalence/intensity, and pain medication use; HRQoL was evaluated using the 36-Item Short-Form Health Survey version 2 (SF-36v2). Safety data were collected throughout the study. All 14 patients (11 women) had compound heterozygous ALPL gene mutations and ≥1 HPP bone manifestation, including history of ≥1 fracture. Mean (min, max) age was 51 (19 to 78) years. From baseline to 12 months of treatment, median 6MWT distance increased from 267 m to 320 m (n = 13; p = 0.023); median TUG test time improved from 14.4 s to 11.3 s (n = 9; p = 0.008). Specific components of the SPPB also improved significantly: median 4-m gait speed increased from 0.8 m/s to 1.1 m/s (n = 10; p = 0.007) and median repeated chair-rise time improved from 22 s to 13 s (n = 9; p = 0.008). LEFS score improved from 24 points to 53 points (n = 10; p = 0.002). Improvements in HHD were not clinically significant. SF-36v2 Physical Component Score (PCS) improved after 12 months of treatment (n = 9; p = 0.010). Pain level did not change significantly from baseline to 12 months of treatment. There were significant improvements on chair-rise time and SF-36v2 PCS by 3 months, and on TUG test time after 6 months. No new safety signals were identified. These results show the real-world effectiveness of asfotase alfa in improving physical functioning and HRQoL in adults with pediatric-onset HPP. © 2020 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Burden of Illness in Adults With Hypophosphatasia: Data From the Global Hypophosphatasia Patient Registry.

Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by deficient tissue non-specific alkaline phosphatase activity. This study aims to assess patient-reported pain, disability and health-related quality of life (HRQoL) in a real-world cohort of adults with HPP who were not receiving asfotase alfa during the analysis. Adults (≥18 years old) with HPP (confirmed by ALPL gene mutation and/or low serum alkaline phosphatase activity for age/sex) were identified from the Global HPP Registry (NCT02306720). Demographics, clinical characteristics, and data on patient-reported pain, disability, and HRQoL (assessed by Brief Pain Inventory Short Form [BPI-SF], Health Assessment Questionnaire Disability Index [HAQ-DI], and 36-Item Short-Form Health Survey version 2 [SF-36v2], respectively) were stratified by pediatric- and adult-onset HPP and summarized descriptively. Of the 304 adults included (median [min, max] age 48.6 [18.8, 79.8] years; 74% women), 45% had adult-onset HPP and 33% had pediatric-onset HPP (unknown age of onset, 22%). Of those with data, 38% had experienced ≥5 HPP manifestations and 62% had a history of ≥1 fracture/pseudofracture. Median (Q1, Q3) BPI-SF scores were 3.5 (1.5, 5.3) for pain severity and 3.3 (0.9, 6.2) for pain interference. Median (Q1, Q3) disability on the HAQ-DI was 0.3 (0.0, 0.7). Median (Q1, Q3) physical and mental component summary scores on the SF-36v2 were 42.4 (32.7, 49.9) and 45.3 (36.3, 54.8), respectively. Greater numbers of HPP manifestations experienced/body systems affected correlated significantly with poorer scores on the BPI-SF, HAQ-DI, and SF-36v2 (all p < 0.05). No significant differences between adults with pediatric- and adult-onset HPP were observed for patient-reported outcomes, except for disability and the BPI-SF question "pain at its worst," which were significantly higher among adults with pediatric- versus adult-onset HPP (p = 0.03 and 0.04, respectively). These data from the Global HPP Registry show that adults with HPP have a substantial burden of illness that is associated with reduced patient-reported HRQoL, regardless of age of disease onset. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dual X-ray absorptiometry has limited utility in detecting bone pathology in children with hypophosphatasia: A pooled post hoc analysis of asfotase alfa clinical trial data.

Asfotase alfa is an enzyme replacement therapy approved for treatment of patients with pediatric-onset hypophosphatasia (HPP), a rare, inherited, systemic disease causing impaired skeletal mineralization, short stature, and reduced physical function in children. The role of dual X-ray absorptiometry (DXA) in the assessment of children with HPP has been insufficiently explored. This post hoc analysis included pooled DXA data from 2 open-label, multicenter studies in 19 children with HPP. The study population was aged ≥5 to <18 years and had received asfotase alfa for ≤6.6 years at enrollment (male: 79%; median age at enrollment: 10.4 y [range: 5.9-16.7]; treatment duration: 6.3 y [range: 0.1-6.6]. Baseline height Z-scores indicated short stature (median [min, max]: -1.26 [-6.6, 0]); mean [SD]: -2.30 [1.97]), thus requiring height adjustment of DXA Z-scores. At Baseline, few patients had height-adjusted bone mineral density (BMDht) Z-scores of -2 or less for whole body (n = 3) or lumbar spine (n = 5). In treated patients, mean whole body and lumbar spine BMDhtZ-scores did not change over time, but whole body and lumbar spine height- adjusted bone mineral content (BMCht) Z-scores increased significantly from Baseline to Last Assessment (P ≤ 0.0056). Improvements in Radiographic Global Impression of Change (RGI-C) scale scores correlated significantly with increases in whole body and lumbar spine BMChtZ-scores (P < 0.05) but not BMDhtZ-Scores. Improvements in Rickets Severity Score (RSS) correlated significantly with increases in lumbar spine BMDhtZ-scores and whole body BMCht Z-scores (P < 0.05). No significant correlations were observed between any DXA and bone histomorphometry measure. These findings suggest that DXA BMD Z-scores, which are commonly used in clinical practice, have limited utility in assessing deficient bone mineralization in patients with HPP. Although BMChtZ-scores increased significantly over time with asfotase alfa therapy, the lack of significant changes in more than one DXA parameter suggests that this tool may not be useful in everyday clinical practice. Furthermore, the use of BMC as an independent metric is not typical or recommended by guidelines. Complementary measures, such as skeletal radiographs supplemented with age-appropriate functional assessments, should be considered.

Early characteristics of bone deficits in children with Fontan palliation.

BACKGROUND: This is a cross-sectional study aiming to understand the early characteristics and background of bone health impairment in clinically well children with Fontan circulation. METHODS: We enrolled 10 clinically well children with Fontan palliation (operated >5 years before study entrance, Tanner stage ≤3, age 12.1 ± 1.77 years, 7 males) and 11 healthy controls (age 12.0 ± 1.45 years, 9 males) at two children's hospitals. All patients underwent peripheral quantitative CT. For the Fontan group, we obtained clinical characteristics, NYHA class, cardiac index by MRI, dual x-ray absorptiometry, and biochemical studies. Linear regression was used to compare radius and tibia peripheral quantitative CT measures between Fontan patients and controls. RESULTS: All Fontan patients were clinically well (NYHA class 1 or 2, cardiac index 4.85 ± 1.51 L/min/m2) and without significant comorbidities. Adjusted trabecular bone mineral density, cortical thickness, and bone strength index at the radius were significantly decreased in Fontan patients compared to controls with mean differences -30.13 mg/cm3 (p = 0.041), -0.31 mm (p = 0.043), and -6.65 mg2/mm4 (p = 0.036), respectively. No differences were found for tibial measures. In Fontan patients, the mean height-adjusted lumbar bone mineral density and total body less head z scores were -0.46 ± 1.1 and -0.63 ± 1.1, respectively, which are below the average, but within normal range for age and sex. CONCLUSIONS: In a clinically well Fontan cohort, we found significant bone deficits by peripheral quantitative CT in the radius but not the tibia, suggesting non-weight-bearing bones may be more vulnerable to the unique haemodynamics of the Fontan circulation.

Burden of disease in pediatric patients with hypophosphatasia: results from the HPP Impact Patient Survey and the HPP Outcomes Study Telephone interview.

BACKGROUND: Hypophosphatasia (HPP) is a rare, inherited, metabolic bone disease caused by deficient tissue-non-specific isoenzyme of alkaline phosphatase activity that manifests as a broad range of signs/symptoms, including bone mineralization defects and systemic complications. The burden of disease is poorly characterized, particularly in children. This study aimed to characterize the patient-reported burden of disease among children with HPP using two survey instruments: the HPP Impact Patient Survey (HIPS) and the HPP Outcomes Study Telephone interview (HOST). METHODS: Between September 2009 and June 2011, pediatric patients (aged younger than 18 years) with HPP were recruited to participate in the study via patient advocacy groups or their medical provider. Survey questions were used to capture information on patient demographics, HPP-related medical history, mobility, and health-related quality of life (HRQoL; using the 10-item Short-Form Health Survey for Children [SF-10], HIPS only). RESULTS: Common clinical features of the 59 pediatric survey respondents (mean [standard deviation] age: 7.6 [5.1] years; 51% male) included pain (86% of patients), muscle weakness (71%), difficulty gaining weight (64%), and delayed walking (59%). Fracture was reported by 36% of patients; multiple fractures were also reported (15% of patients). Use of assistive devices for mobility was frequent among the study population (51%). In response to the SF-10, patients reported a substantial impact of HPP on their HRQoL; physical function was the most severely impaired component relative to normative data. Of patients responding to the HOST, two-thirds experienced worsening of at least one of their HPP-related signs/symptoms over a 5-year period. CONCLUSIONS: In pediatric patients, HPP is associated with a high burden of disease and a substantial negative impact on HRQoL. The burden of HPP may increase and HRQoL reduce further over time as signs/symptoms that affect HRQoL worsen or new signs/symptoms manifest.

Use of an aromatase inhibitor in children with congenital adrenal hyperplasia: Impact of anastrozole on bone mineral density and visceral adipose tissue.

OBJECTIVE: Anastrozole, an aromatase inhibitor, has been used off-label in males with short stature to delay bone maturation. No studies have examined anastrozole's effect on bone mineral density (BMD) or body composition in children with congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. Our objective was to evaluate anastrozole's effect on BMD and visceral adipose tissue (VAT) in children with CAH. DESIGN: Total body BMD (TBMD) and L2-L4 BMD Z-scores were adjusted for height-for-age Z-scores (TBMDHAZ and L2-L4HAZ ). Hydrocortisone doses (mg/m2 /d) were averaged over the previous year. Comparison of treated vs not treated with anastrozole used linear regression adjusting for age, pubertal status, sex, CAH type, years on hydrocortisone, BMI Z-scores and bone age Z-scores. PATIENTS: We compared 25 children with CAH treated with anastrozole (mean age 11.3 [SD 3.0] years, 56% males) vs 31 children with CAH not treated with anastrozole (13.5 [SD 4.6], 29%). Participants underwent a pubertal exam, bone age X-ray and dual X-ray absorptiometry (DXA) scan. RESULTS: Average bone age Z-score of 4.3 SDs on beginning anastrozole decreased to 1.9 SDs at time of DXA exam (P = 0.0004) 5.2 (SD 2.2) years later. TBMD Z-scores (P = 0.51), L2-L4 BMD Z-scores (P = 0.66), VAT (P = 0.38), TBMDHAZ Z-scores (P = 0.66) and L2-L4HAZ Z-scores (P = 0.41) did not differ between children treated vs not treated with anastrozole. CONCLUSION: Anastrozole significantly reduced bone age advancement in children with CAH and advanced bone age (>2SDs) without adverse effects on BMD or VAT. Longitudinal studies of anastrozole in children with CAH are needed to validate these findings.

Frequency and age at occurrence of clinical manifestations of disease in patients with hypophosphatasia: a systematic literature review.

BACKGROUND: Hypophosphatasia (HPP) is a rare, inherited, metabolic disease caused by tissue-nonspecific alkaline phosphatase deficiency, characterized by bone mineralization defects and systemic complications. Understanding of the clinical course and burden of HPP is limited by its rarity. This systematic literature review and synthesis of case report data aimed to determine the frequency and timing of clinical HPP manifestations and events. METHODS: Case reports and series of patients with HPP who had been followed longitudinally for ≥1 year were identified. Demographics and clinical data of interest, identified through consultation with clinical experts in HPP, were extracted. Occurrences of clinical manifestations/events of interest were categorized, classified by age at first reported occurrence of HPP manifestations and visualized over time. Clinical manifestations/events considered to contribute to the clinical burden of HPP were identified. Kaplan-Meier curves were used to estimate the median (range) age at first occurrence of the most frequently reported manifestations/events. RESULTS: From the 283 studies that met the inclusion criteria, 265 patients with HPP with ≥1 year of longitudinal follow-up were identified (median [interquartile range] age 4 [0-34] years; 45% male). The types of clinical manifestations/events of interest experienced by individuals with ≥1 such manifestation/event (n = 261) often differed between older and younger patients. Most (94%) of the 265 patients experienced ≥1 manifestation/event deemed to contribute to the clinical burden of HPP; premature tooth loss (53.5%), fractures (35.8%), pain (33.6%), and gross motor/ambulation difficulties (30.9%) were most frequently reported. The median (range) age at first reported occurrence of respiratory symptoms, cranial abnormalities, and premature tooth loss ranged from 0.3 to 10 years, whereas the median age at first reported occurrence of fractures, pain, gross motor/ambulation difficulties, and surgery ranged from 33 to 70 years. CONCLUSIONS: HPP is associated with a high clinical burden of disease, regardless of age at first reported occurrence of HPP manifestations. Over an individual's lifetime, the types of manifestations/events experienced can change and multiple HPP-related clinical manifestations/events can accumulate. These observations may reflect evolution and progression of the disease.

Diagnostic delay is common among patients with hypophosphatasia: initial findings from a longitudinal, prospective, global registry.

BACKGROUND: Hypophosphatasia (HPP) is a rare, systemic disease caused by mutation(s) within the ALPL gene encoding tissue-nonspecific alkaline phosphatase (ALP). HPP has a heterogeneous presentation, which coupled with its rarity, often leads to missed/delayed diagnosis and an incomplete understanding of its natural history. To better understand the epidemiology and clinical course of HPP, including timing of diagnosis after first reported manifestation, we present baseline data for patients enrolled in the Global HPP Registry. METHODS: Data were analyzed from patients with an HPP diagnosis confirmed by low serum ALP activity and/or an ALPL pathogenic variant, regardless of prior or current treatment, according to age at enrollment (children: < 18 y; adult: ≥18 y). All analyses were descriptive. RESULTS: Of 269 patients from 11 countries enrolled January 2015-September 2017, 121 (45.0%) were children and 148 (55.0%) were adults. The majority of children and adults were female (61.2 and 73.0%, respectively) and white (57.7 and 90.0%, respectively). Children had a median (min, max) age at earliest reported HPP manifestation of 7.2 months (- 2.3 mo, 16.0 y), which was > 12 months before diagnosis at age 20.4 months (- 0.2 mo, 16.0 y). In adults, the earliest reported manifestation occurred at a median (min, max) age of 37.6 years (0.2 y, 75.2 y), which preceded age at diagnosis (47.5 years [0.2 y, 75.2 y]) by ~ 10 years. Premature loss of deciduous teeth (48.2%, age ≥ 6 mo), bone deformity (32.5%), and failure to thrive (26.7%) were most commonly reported in the HPP-related disease history of children. Pain (74.5%), orthopedic procedures and therapies (44.6%), and recurrent and poorly healing fractures (36.5%) were most commonly reported in the HPP-related disease history of adults. CONCLUSIONS: The Global HPP Registry represents the largest observational study of patients with HPP, capturing real world data. This analysis shows that diagnostic delay is common, reflecting limited awareness of HPP, and that HPP is associated with systemic manifestations across all ages. Many patients diagnosed in adulthood had HPP manifestations in childhood, highlighting the importance of taking thorough medical histories to ensure timely diagnosis. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02306720 , December 2014; ENCePP.eu: EUPAS13526 , May 2016 (retrospectively registered).