Search

Abstract 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.

Abstract Background Growth hormone deficiency (GHD) is the commonest endocrine cause of short stature and may occur in isolation (I-GHD) or combined with other pituitary hormone deficiencies. Around 500 children are diagnosed with GHD every year in the UK, of whom 75% have I-GHD. Growth hormone (GH) therapy improves growth in children with GHD, with the goal of achieving a normal final height (FH). GH therapy is given as daily injections until adult FH is reached. However, in many children with I-GHD their condition reverses, with a normal peak GH detected in 64–82% when re-tested at FH. Therefore, at some point between diagnosis and FH, I-GHD must have reversed, possibly due to increase in sex hormones during puberty. Despite increasing evidence for frequent I-GHD reversal, daily GH injections are traditionally continued until FH is achieved. Methods/design Evidence suggests that I-GHD children who re-test normal in early puberty reach a FH comparable to that of children without GHD. The GHD Reversal study will include 138 children from routine endocrine clinics in twelve UK and five Austrian centres with I-GHD (original peak GH

Abstract Background Collection of real-world evidence (RWE) is important in achondroplasia. Development of a prospective, shared, international resource that follows the principles of findability, accessibility, interoperability, and reuse of digital assets, and that captures long-term, high-quality data, would improve understanding of the natural history of achondroplasia, quality of life, and related outcomes. Methods The Europe, Middle East, and Africa (EMEA) Achondroplasia Steering Committee comprises a multidisciplinary team of 17 clinical experts and 3 advocacy organization representatives. The committee undertook an exercise to identify essential data elements for a standardized prospective registry to study the natural history of achondroplasia and related outcomes. Results A range of RWE on achondroplasia is being collected at EMEA centres. Whereas commonalities exist, the data elements, methods used to collect and store them, and frequency of collection vary. The topics considered most important for collection were auxological measures, sleep studies, quality of life, and neurological manifestations. Data considered essential for a prospective registry were grouped into six categories: demographics; diagnosis and patient measurements; medical issues; investigations and surgical events; medications; and outcomes possibly associated with achondroplasia treatments. Conclusions Long-term, high-quality data are needed for this rare, multifaceted condition. Establishing registries that collect predefined data elements across age spans will provide contemporaneous prospective and longitudinal information and will be useful to improve clinical decision-making and management. It should be feasible to collect a minimum dataset with the flexibility to include country-specific criteria and pool data across countries to examine clinical outcomes associated with achondroplasia and different therapeutic approaches.

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

Abstract Osteogenesis imperfecta (OI) is a genetically and clinically heterogeneous disorder characterized by bone fragility and reduced bone mass generally caused by defects in type I collagen structure or defects in proteins interacting with collagen processing. We identified a homozygous missense mutation in SEC16B in a child with vertebral fractures, leg bowing, short stature, muscular hypotonia, and bone densitometric and histomorphometric features in keeping with OI with distinct ultrastructural features. In line with the putative function of SEC16B as a regulator of trafficking between the ER and the Golgi complex, we showed that patient fibroblasts accumulated type I procollagen in the ER and exhibited a general trafficking defect at the level of the ER. Consequently, patient fibroblasts exhibited ER stress, enhanced autophagosome formation, and higher levels of apoptosis. Transfection of wild‐type SEC16B into patient cells rescued the collagen trafficking. Mechanistically, we show that the defect is a consequence of reduced SEC16B expression, rather than due to alterations in protein function. These data suggest SEC16B as a recessive candidate gene for OI.

Summary: 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.

BackgroundDietary intake is widely known to play a crucial role in achieving peak bone mass among children and adolescents. Unfortunately, this information is lacking among Arab adolescents, an understudied demographic that has recently been observed to have a high prevalence of abnormal mineralization markers [low serum 25(OH)D, high serum alkaline phosphatase (ALP), low calcium (Ca) and/or inorganic phosphate (Pi)] suggestive of biochemical osteomalacia (OM, defined as any 2 of the 4 parameters). In order to fill this gap, we aimed to evaluate the associations of serum markers of biochemical OM with dietary intake of macronutrients, vitamins and trace minerals.MethodsSaudi adolescents (N = 2,938, 57.8% girls), aged 12–17 years from 60 different schools in Riyadh, Saudi Arabia were included. Dietary intake of nutrients was calculated following a semi-quantitative 24 h dietary recall over 3 weekdays and 1 weekend-day using a validated food frequency questionnaire. Compliance to reference daily intake (RDI) of macronutrients, vitamins and trace minerals were calculated. Fasting blood samples were collected and circulating levels of 25(OH)D, ALP, Ca, and Pi were analyzed.ResultsA total of 1819 (1,083 girls and 736 boys) adolescents provided the dietary recall data. Biochemical OM was identified in 175 (9.6%) participants (13.5% in girls, 3.9% in boys, p 50 nmol/L) but they exceed the RDI for dietary Pi. Interpreting these data in the light of the increased prevalence of rickets in Arab countries, food fortification to optimise vitamin D and Ca intake in Saudi adolescents should be considered.

Bi-allelic variants in ASCC1 cause the ultrarare bone fragility disorder “spinal muscular atrophy with congenital bone fractures-2” (SMABF2). However, the mechanism by which ASCC1 dysfunction leads to this musculoskeletal condition and the nature of the associated bone defect are poorly understood. By exome sequencing, we identified a novel homozygous deletion in ASCC1 in a female infant. She was born with severe muscular hypotonia, inability to breathe and swallow, and virtual absence of spontaneous movements; showed progressive brain atrophy, gracile long bones, very slender ribs, and a femur fracture; and died from respiratory failure aged 3 months. A transiliac bone sample taken postmortem revealed a distinct microstructural bone phenotype with low trabecular bone volume, low bone remodeling, disordered collagen organization, and an abnormally high bone marrow adiposity. Proteomics, RNA sequencing, and qPCR in patient-derived skin fibroblasts confirmed that ASCC1 was hardly expressed on protein and RNA levels compared with healthy controls. Furthermore, we demonstrate that mutated ASCC1 is associated with a downregulation of RUNX2, the master regulator of osteoblastogenesis, and SERPINF1, which is involved in osteoblast and adipocyte differentiation. It also exerts an inhibitory effect on TGF-β/SMAD signaling, which is important for bone development. Additionally, knockdown of ASCC1 in human mesenchymal stromal cells (hMSCs) suppressed their differentiation capacity into osteoblasts while increasing their differentiation into adipocytes. This resulted in reduced mineralization and elevated formation of lipid droplets. These findings shed light onto the pathophysiologic mechanisms underlying SMABF2 and assign a new biological role to ASCC1 acting as an important pro-osteoblastogenic and anti-adipogenic regulator.

Abstract 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.

IntroductionHypophosphatasia (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.MethodsBaseline/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).ResultsOf 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

Loss-of-function mutations in SMAD3 cause Loeys-Dietz syndrome type 3 (LDS3), a rare autosomal-dominant connective tissue disorder characterized by vascular pathology and skeletal abnormalities. Dysregulation of TGF-β/SMAD signaling is associated with abnormal skeletal features and bone fragility. To date, histomorphometric and ultrastructural characteristics of bone with SMAD3 mutations have not been reported in humans and the exact mechanism by which SMAD3 mutations cause the LDS3 phenotype is poorly understood. Here, we investigated bone histomorphometry and matrix mineralization in human bone with a SMAD3 mutation and explored the associated cellular defect in the TGF-β/SMAD pathway in vitro. The index patient had recurrent fractures, mild facial dysmorphism, arachnodactyly, pectus excavatum, chest asymmetry and kyphoscoliosis. Bone histomorphometry revealed markedly reduced cortical thickness (−68 %), trabecular thickness (−32 %), bone formation rate (−50 %) and delayed mineralization. Quantitative backscattered electron imaging demonstrated undermineralized bone matrix with increased heterogeneity in mineralization. The patient's SMAD3 mutation (c.200 T > G; p.I67S), when expressed from plasmid vectors in HEK293 cells, showed reduced phosphorylation and transcription factor activity compared to normal control and SMAD3 (p.S264Y), a gain-of-function mutation, somatic mosaicism of which causes melorheostosis. Transfection study of the patients' SMAD3 (p.I67S) mutation displayed lower luciferase reporter activity than normal SMAD3 and reduced expression of TGF-β signaling target genes. Patient fibroblasts also demonstrated impaired SMAD3 protein stability. Osteoclastogenic differentiation significantly increased and osteoclast-associated genes, including ACP5 (encoding TRAP), ATP6V0D2, and DCSTAMP, were up-regulated in CD14 (+) peripheral blood mononuclear cells (PBMCs) with the SMAD3 (p.I67S) mutation. Upregulation of osteoclastogenic genes was associated with decreased expression of TGF-β signaling target genes. We conclude that bone with the SMAD3 (p.I67S) mutation features reduced bone formation, and our functional studies revealed decreased SMAD3 activation and protein stability as well as increased osteoclastogenesis. These findings enhance our understanding of the pathophysiology of LDS3 caused by SMAD3 mutations. Emerging therapies targeting in the TGF-β/SMAD pathway also raise hope for treatment of LDS3.

ObjectivesVitamin D deficiency in neonates can have life-threatening consequences, hence the knowledge of risk factors is essential. This study aimed to explore the effect of maternal socioeconomic status (SES) on newborn 25-hydroxyvitamin D (25OHD) concentrations.DesignOver two 1-week periods (winter and summer of 2019), 3000 newborn heel prick dried blood spots (DBS) and additional data of newborns, from a regional newborn screening laboratory (52° N) in the West Midlands, UK, were gathered. Post code was replaced with lower layer super output area (LSOA). Index of Multiple Deprivation (IMD) quintiles for the corresponding LSOA was used to assess SES [quintile one (Q1): most deprived 20%, quintile five (Q5): least deprived 20%]. Each of the seven domains of deprivation were examined (income, employment, education, health, barriers to housing and services, crime and living environment). 25OHD was measured on 6mm sub-punch from DBS using quantitative liquid chromatography tandem mass spectrometry and equivalent plasma values were derived.ResultsIn total 2999 (1500 summer-born, 1499 winter-born) newborn DBS (1580 males) were analysed. Summer-born newborns had significantly higher 25OHD (IQR) concentrations [49.2 (34.3; 64.8) nmol/l] than winter-born newborns [29.1 (19.8; 40.6) nmol/l, p

BackgroundMicronutrient deficiencies are common among household/family members due to shared lifestyle and dietary habits. The extent of biochemical abnormalities in household members of children presenting with symptomatic vitamin D deficiency remains unknown.AimInvestigate the prevalence of vitamin D deficiency and biochemical osteomalacia in the mothers and siblings of children presenting with symptomatic vitamin D deficiency.MethodsAll mothers and sibling of children referred to a single tertiary endocrine centre between January 2018 and December 2021, with symptomatic vitamin D deficiency were investigated prospectively for vitamin D deficiency [defined as 25 hydroxyvitamin D (25OHD) < 30nmol/L] and biochemical osteomalacia [vitamin D deficiency and elevated alkaline phosphatase (ALP) and/or parathormone (PTH)] as per clinical guidelines.ReultsNinety-seven family members (68 siblings and 29 mothers) of 29 index cases (median age 1.7 years, 55.5% male) were investigated. The majority (65.5%, n=19) were of Asian ethnic background. The mean (SD) 25OHD levels of the index, maternal and sibling cohorts were 15 (10), 15 (7) and 20 (10) nmol/L respectively. Vitamin D deficiency was noted in 93% of the maternal and 79% of the sibling cohorts. Biochemical osteomalacia was present in 72% of the maternal and 79% of the sibling cohorts. Mothers of infants had significantly lower mean 25OHD levels compared to mothers of older children [11 (n=12) vs 18 nmol/L (n=17) respectively, p=0.006)], most of whom were symptomatic (66.6%, n=8/12). None of the mothers had hypocalcaemia. Among the 10% (n=7) of the siblings with hypocalcaemia, 86% (n=6/7) had concurrent dietary calcium deficiency and 71.4% (n= 5/7) reported symptoms in retrospect. Hypocalcaemic siblings had significantly lower 25OHD (7 vs 15 nmol/L, p

Background: Vertebral compression fractures (VFs) are a common and severe finding in patients with osteoporosis. In children, VFs have the unique potential to reshape and regain their original configuration. Spontaneous vertebral body reshaping (i.e., medication-unassisted) has been reported in secondary osteoporosis. Here we describe a previously unreported spontaneous vertebral reshaping in an adolescent with osteogenesis imperfecta (OI) with multiple vertebral fractures. Case report: A 17-year-old female was diagnosed with OI type I at 5 years of age caused by a novel frameshift variant in COL1A1 (NM_000088.4: c.540delC; p.Met181TrpfsTer84). Due to parental reservations about medication, she had never received bisphosphonate or any other bone active therapy. A lateral spine X-ray demonstrated transparent bones and no VF. However, previous spine X-rays taken at age of 6 years at an external institution showed VFs in T5–7 (Genant semiquantitative method grade I-II). The two lateral spine x-rays, taken 11 years apart, demonstrate that substantial spontaneous vertebral reshaping occurred without bone active therapy during puberty. Discussion: Vertebral reshaping is explained by the stabilization of bone mineral density (BMD) and the remaining growth capacity the children. We hypothesize that spontaneous reshaping may occur in milder forms of OI, and that puberty may be a key mediator of the phenomenon. In all children with OI and vertebral fractures, we nevertheless recommend bisphosphonate therapy since it improves bone mass, BMD, vertebral shape, physical activity and reduces fracture rates.

Mutations in components of the MAP kinase pathway are associated with a group of syndromes known as RASopathies. Here, the authors identify gain-of-function mutations in BRAF in patients with RASopathies and congenital hypopituitarisms. This article demonstrates a central role for BRAF in the development of the hypothalamo-pituitary axis leading to endocrine deficiencies in patients with RASopathies.

A synoptic overview of scientific methods applied in bone and associated research fields across species has yet to be published. Experts from the EU Cost Action GEMSTONE (“GEnomics of MusculoSkeletal Traits translational Network”) Working Group 2 present an overview of the routine techniques as well as clinical and research approaches employed to characterize bone phenotypes in humans and selected animal models (mice and zebrafish) of health and disease. The goal is consolidation of knowledge and a map for future research. This expert paper provides a comprehensive overview of state-of-the-art technologies to investigate bone properties in humans and animals – including their strengths and weaknesses. New research methodologies are outlined and future strategies are discussed to combine phenotypic with rapidly developing –omics data in order to advance musculoskeletal research and move towards “personalised medicine”.

Osteogenesis imperfecta (OI) is an inherited genetic disorder characterized by frequent bone fractures and reduced bone mass. Most cases of OI are caused by dominantly inherited heterozygous mutations in one of the two genes encoding type I collagen, COL1A1 and COL1A2. Here we describe a five-year-old boy with typical clinical, radiological and bone ultrastructural features of OI type I. Establishing the molecular genetic cause of his condition proved difficult since clinical exome and whole exome analysis was repeatedly reported negative. Finally, manual analysis of exome data revealed a silent COL1A2 variant c.3597 T > A (NM_000089.4), which we demonstrate activates a cryptic splice site. The newly generated splice acceptor in exon 50 is much more accessible than the wild-type splice-site between the junction of exon 49 and 50, and results in an in-frame deletion of 24 amino acids of the C-terminal propeptide. In vitro collagen expression studies confirmed cellular accumulation and decreased COL1A2 secretion to 45%. This is the first report of a cryptic splice site within the coding region of COL1A2. which results in abnormal splicing causing OI. The experience from this case demonstrates that routine diagnostic approaches may miss cryptic splicing mutations in causative genes due to the lack of universally applicable algorithms for splice-site prediction. In exome-negative cases, in-depth analysis of common causative genes should be conducted and trio-exome analysis is recommended.

Nutrition-acquired osteomalacia is a bone mineralization disorder associated with dietary calcium and/or solar vitamin D deficiency, risk factors considered common in the Middle Eastern region. Establishing less invasive, cheap, and widely available diagnostic markers for this underdiagnosed entity is essential, in particular for screening in high-risk groups. This study assessed the prevalence of biochemical osteomalacia in Arab adolescents. In this cross-sectional study performed between September 2019 and March 2021, adolescents aged 12–17 years from 60 different secondary and preparatory year schools in Riyadh, Saudi Arabia were included. Anthropometrics and fasting blood samples were collected. Biochemical osteomalacia was defined as any two of the following four serum markers of hypomineralization, namely low 25 hydroxyvitamin D (25OHD < 30 nmol/L), high alkaline phosphatase (ALP), low calcium (Ca), and/or inorganic phosphorous (Pi). A total of 2938 Arab adolescents [1697 girls; mean age (years) 14.8 ± 1.8; 1241 boys; mean age 15.1 ± 1.6] were recruited. Vitamin D deficiency was noted in 56.2% (n = 953) of girls and 27.1% (n = 336) of boys (p < 0.001). The overall prevalence of biochemical osteomalacia was 10.0% (n = 295/2938) and was higher in girls than boys (14.7% vs. 3.6%, p < 0.001). The prevalence of low serum Ca and/or Pi was also higher in girls than in boys (24.2% vs. 12.5%, respectively, p < 0.001), as well as elevated ALP (5.1% vs. 1.5%, p < 0.001). Overall, girls were 4.6 times (95% CI 3.3–6.4) more likely to have biochemical osteomalacia than boys. Screening of apparently healthy Arab adolescents revealed a high prevalence of deranged mineralization markers suggestive of biochemical osteomalacia, which was significantly more common in girls than boys and was likely associated with Arab traditional clothing and diet. The proposed combination of typically altered mineralization markers for the diagnosis of osteomalacia is, at best, suggestive until further comparisons with established diagnostic tools (histological analysis of bone biopsies) are conducted.

Background: Early exposure to digital media may affect the physical and cognitive development in young children. The American Academy of Pediatrics and national guidelines recommend no digital media use at all under the age of 18 months. The aim of our study was to determine the actual exposure to digital media in 12-month-old infants and to reveal potential risk factors for screen time.Methods: In this prospective cross-sectional survey, data was collected from the KUNO Kids birth cohort study using parent-report questionnaires regarding the media exposure of the study child. We determined age at first contact with different digital media, mean screen time on an average weekday, and the influence of major demographic and socioeconomic factors.Results: Data for screen time analysis was available for 630 children. In summary, 45% of children had already been exposed to digital media by their first birthday. The most frequent first digital media exposure was the TV (33.0%) followed by smartphones (16.9%), both most commonly exposed to around the age of 8 months. On a regular weekday, 20% of the children spent 0.5–1 h in front of a TV and 9% were exposed to a smartphone for the same time frame, compared to 31% of joint parent-child media use. Predictors for screen time were having one sibling, less living space per person, and excessive TV use in the household, the latter of which doubled the chance of the child being exposed to digital media.Conclusion: A proportion of 10% of 1-year-old children were already regularly exposed to digital media. The TV remains the most predominant device but new media, particularly smartphones, might be catching up. Our study provides further support that family TV time is a major predictor of infant screen time. Pediatric recommendations should be re-evaluated in the light of the actual exposure to digital media already in infancy and parents should be proactively counseled regarding possible effects on child development.

Familial hypocalciuric hypercalcemia (FHH, [OMIM #145980]) is recognized as a benign endocrine condition affecting PTH and calcium levels due to heterozygous inactivating mutations in the calcium sensing receptor (CaSR). The condition is often un- or misdiagnosed but may have a prevalence as high as 74 in 100.000. Here, the neonatal courses of two brothers with paternally inherited FHH (CaSR c.554G>A; p.(Arg185Gln)) are described. The older brother was born preterm at 25 weeks gestation with hypercalcemia and hyperparathyroidism. The younger brother, born full-term, had severe hyperparathyroidism, muscular hypotonia, thrombocytopenia, failure to thrive and multiple metaphyseal fractures. Treatment with cinacalcet was initiated, which resulted in subsequent reduction of PTH levels and prompt clinical improvement. While it is known that homozygous mutations in CaSR may lead to life-threatening forms of neonatal severe hyperparathyroidism (NSHPT), few reports have described a severe clinical course in neonates with FHH due to heterozygous mutations. However, based on the pathophysiological framework, in de novo or paternally transmitted FHH the differing calcium needs of mother and fetus can be expected to induce fetal hyperparathyroidism and may result in severe perinatal complications as described in this report. In summary, FHH is a mostly benign condition, but transient neonatal hyperparathyroidism may occur in affected neonates if the mutation is paternally inherited. If severe, the condition can be treated successfully with cinacalcet. Patients with FHH should be informed about the risk of neonatal disease manifestation in order to monitor pregnancies and neonates.

Genetic disorders of the skeleton encompass a diverse group of bone diseases differing in clinical characteristics, severity, incidence and molecular etiology. Of particular interest are the monogenic rare bone mass disorders, with the underlying genetic defect contributing to either low or high bone mass phenotype. Extensive, deep phenotyping coupled with high-throughput, cost-effective genotyping is crucial in the characterization and diagnosis of affected individuals. Massive parallel sequencing efforts have been instrumental in the discovery of novel causal genes that merit functional validation using in vitro and ex vivo cell-based techniques, and in vivo models, mainly mice and zebrafish. These translational models also serve as an excellent platform for therapeutic discovery, bridging the gap between basic science research and the clinic. Altogether, genetic studies of monogenic rare bone mass disorders have broadened our knowledge on molecular signaling pathways coordinating bone development and metabolism, disease inheritance patterns, development of new and improved bone biomarkers, and identification of novel drug targets. In this comprehensive review we describe approaches to further enhance the innovative processes taking discoveries from clinic to bench, and then back to clinic in rare bone mass disorders. We highlight the importance of cross laboratory collaboration to perform functional validation in multiple model systems after identification of a novel disease gene. We describe the monogenic forms of rare low and high rare bone mass disorders known to date, provide a roadmap to unravel the genetic determinants of monogenic rare bone mass disorders using proper phenotyping and genotyping methods, and describe different genetic validation approaches paving the way for future treatments.

Abstract 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: 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).

Abstract Background Whilst hypocalcemic complications from vitamin D deficiency are considered rare in high-income countries, they are highly prevalent among Black, Asian and Minority Ethnic (BAME) group with darker skin. To date, the extent of osteomalacia in such infants and their family members is unknown. Our aim was to investigate clinical, cardiac and bone histomorphometric characteristics, bone matrix mineralization in affected infants and to test family members for biochemical evidence of osteomalacia. Case presentation Three infants of BAME origin (aged 5–6 months) presented acutely in early-spring with cardiac arrest, respiratory arrest following seizure or severe respiratory distress, with profound hypocalcemia (serum calcium 1.22–1.96 mmol/L). All infants had dark skin and vitamin D supplementation had not been addressed during child surveillance visits. All three had severely dilated left ventricles (z-scores + 4.6 to + 6.5) with reduced ejection fraction (25–30%; normal 55–70), fractional shortening (7 to 15%; normal 29–40) and global hypokinesia, confirming hypocalcemic dilated cardiomyopathy. They all had low serum levels of 25 hydroxyvitamin D (25OHD

In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. Aims: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. Methodology: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5–16 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5–16 years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5–16 years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5–15 years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. Results: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2–L4 BMDa g/cm2), bone mineral apparent density (L2–L4 BMAD g/cm3) and total body less head BMDa (TBLH g/cm2). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. Conclusions: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs.

Background: Nutritional rickets is a growing global public health concern despite existing prevention programmes and health policies. We aimed to compare infant and childhood vitamin D supplementation policies, implementation strategies and practices across Europe and explore factors influencing adherence. Methods: European Society for Paediatric Endocrinology Bone and Growth Plate Working Group members and other specialists completed a questionnaire on country-specific vitamin D supplementation policy and child health care programmes, socioeconomic factors, policy implementation strategies and adherence. Factors influencing adherence were assessed using Kendall’s tau-b correlation coefficient. Results: Responses were received from 29 of 30 European countries (97%). Ninety-six per cent had national policies for infant vitamin D supplementation. Supplements are commenced on day 1–5 in 48% (14/29) of countries, day 6–21 in 48% (14/29); only the UK (1/29) starts supplements at 6 months. Duration of supplementation varied widely (6 months to lifelong in at-risk populations). Good (≥80% of infants), moderate (50–79%) and low adherence (

Protein quality and quantity are important factors in determining lean body (muscle) mass (LBM). In phenylketonuria (PKU), protein substitutes provide most of the nitrogen, either as amino acids (AA) or glycomacropeptide with supplementary amino acids (CGMP-AA). Body composition and growth are important indicators of long-term health. In a 3-year prospective study comparing the impact of AA and CGMP-AA on body composition and growth in PKU, 48 children were recruited. N = 19 (median age 11.1 years, range 5–15 years) took AA only, n = 16 (median age 7.3 years, range 5–15 years) took a combination of CGMP-AA and AA, (CGMP50) and 13 children (median age 9.2 years, range 5–16 years) took CGMP-AA only (CGMP100). A dual energy X-ray absorptiometry (DXA) scan at enrolment and 36 months measured LBM, % body fat (%BF) and fat mass (FM). Height was measured at enrolment, 12, 24 and 36 months. No correlation or statistically significant differences (after adjusting for age, gender, puberty and phenylalanine blood concentrations) were found between the three groups for LBM, %BF, FM and height. The change in height z scores, (AA 0, CGMP50 +0.4 and CGMP100 +0.7) showed a trend that children in the CGMP100 group were taller, had improved LBM with decreased FM and % BF but this was not statistically significant. There appeared to be no advantage of CGMP-AA compared to AA on body composition after 3-years of follow-up. Although statistically significant differences were not reached, a trend towards improved body composition was observed with CGMP-AA when it provided the entire protein substitute requirement.

Bone material strength is determined by several factors, such as bone mass, matrix composition, mineralization, architecture and shape. From a clinical perspective, bone fragility is classified as primary (i.e., genetic and rare) or secondary (i.e., acquired and common) osteoporosis. Understanding the mechanism of rare genetic bone fragility disorders not only advances medical knowledge on rare diseases, it may open doors for drug development for more common disorders (i.e., postmenopausal osteoporosis). In this review, we highlight the main disease mechanisms underlying the development of human bone fragility associated with low bone mass known to date. The pathways we focus on are type I collagen processing, WNT-signaling, TGF-ß signaling, the RANKL-RANK system and the osteocyte mechanosensing pathway. We demonstrate how the discovery of most of these pathways has led to targeted, pathway-specific treatments.

Recessive osteogenesis imperfecta (OI) is caused by defects in proteins involved in post-translational interactions with type I collagen. Recently, a novel form of moderately severe OI caused by null mutations in TMEM38B was identified. TMEM38B encodes the ER membrane monovalent cation channel, TRIC-B, proposed to counterbalance IP3R-mediated Ca2+ release from intracellular stores. The molecular mechanisms by which TMEM38B mutations cause OI are unknown. We identified 3 probands with recessive defects in TMEM38B. TRIC-B protein is undetectable in proband fibroblasts and osteoblasts, although reduced TMEM38B transcripts are present. TRIC-B deficiency causes impaired release of ER luminal Ca2+, associated with deficient store-operated calcium entry, although SERCA and IP3R have normal stability. Notably, steady state ER Ca2+ is unchanged in TRIC-B deficiency, supporting a role for TRIC-B in the kinetics of ER calcium depletion and recovery. The disturbed Ca2+ flux causes ER stress and increased BiP, and dysregulates synthesis of proband type I collagen at multiple steps. Collagen helical lysine hydroxylation is reduced, while telopeptide hydroxylation is increased, despite increased LH1 and decreased Ca2+-dependent FKBP65, respectively. Although PDI levels are maintained, procollagen chain assembly is delayed in proband cells. The resulting misfolded collagen is substantially retained in TRIC-B null cells, consistent with a 50-70% reduction in secreted collagen. Lower-stability forms of collagen that elude proteasomal degradation are not incorporated into extracellular matrix, which contains only normal stability collagen, resulting in matrix insufficiency. These data support a role for TRIC-B in intracellular Ca2+ homeostasis, and demonstrate that absence of TMEM38B causes OI by dysregulation of calcium flux kinetics in the ER, impacting multiple collagen-specific chaperones and modifying enzymes.