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Lodefalk, M. & Nilsson, O. (2025). Persistent Hyperparathyroidism in Vitamin D-Dependent Rickets Type 2A Does Not Prevent Normalization of Hypophosphatemia or Healing of the Rickets. Hormone Research in Paediatrics
Open this publication in new window or tab >>Persistent Hyperparathyroidism in Vitamin D-Dependent Rickets Type 2A Does Not Prevent Normalization of Hypophosphatemia or Healing of the Rickets
2025 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826Article in journal (Refereed) Epub ahead of print
Abstract [en]

INTRODUCTION: Vitamin D-dependent rickets type 2A (VDDR2A) is a rare, autosomal recessive disorder caused by pathogenic variants of the VDR gene encoding the vitamin D receptor. It has been proposed to be a form of parathyroid hormone (PTH)-dependent rickets. Here, we describe in detail a girl with VDDR2A who developed a long-standing, tertiary hyperparathyroidism that did not prevent healing of the rickets nor normalization of hypophosphatemia.

CASE PRESENTATION: A girl who presented with seizures at 9 months of age was diagnosed with VDDR2A. She had poor growth, alopecia, severe hypocalcemia, hypophosphatemia, elevated levels of alkaline phosphatase (ALP), PTH and 1,25-dihydroxyvitamin D, and severe rickets. Genetic studies revealed a novel homozygous microdeletion that included exon 9 of the VDR gene. She responded only partially to high oral doses of calcium, cholecalciferol, and alfacalcidol. Upon the initiation of IV calcium infusions, bone pain resolved, and the rickets healed within weeks. In parallel with decreasing ALP values, her phosphate levels normalized even though her PTH levels remained markedly elevated. PTH levels remained elevated for approximately 1 year after the normalization of S-Ca2+. Calcium infusions, despite rendering her mildly hypercalcemic, mostly failed to suppress her PTH into the normal range, consistent with tertiary hyperparathyroidism. The hyperparathyroidism eventually resolved spontaneously with continued high oral doses of calcium, cholecalciferol, and alfacalcidol, which promoted sustained normocalcemia without the need for either cinacalcet or surgery.

CONCLUSION: Persistent tertiary hyperparathyroidism can develop in children with VDDR2A, but does not seem to prevent the healing of rickets nor normalization of hypophosphatemia. High doses of calcium, preferably administered intravenously, seem to be sufficient for the healing of rickets. We speculate that IV calcium compared to oral calcium increases intestinal phosphorus uptake, and once rickets has healed, improved appetite and dietary phosphorus intake together with reduced phosphorus demands due to saturated bones contribute to the normalization of phosphate levels despite persistent hyperparathyroidism.

Place, publisher, year, edition, pages
S. Karger, 2025
Keywords
Cinacalcet, Hereditary vitamin D-resistant rickets, Hyperparathyroidism, Hypophosphatemia, Vitamin D-dependent rickets type 2A
National Category
Pediatrics Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-121847 (URN)10.1159/000546444 (DOI)40383122 (PubMedID)
Funder
Swedish Research Council, 2021-01807Swedish Society of MedicinePromobilia foundationNyckelfondenStiftelsen Frimurare Barnhuset i StockholmRegion Stockholm, RS2023-0859Karolinska InstituteÖrebro UniversityRegion Örebro County
Note

Funding Agencies:

This work was supported by grants from the Swedish Research Council (project 2021-01807), the Swedish Society of Medicine, Promobilia, Sällsynta Fonden, Nyckelfonden, Stiftelsen Frimurare Barnhuset i Stockholm, the Stockholm County Council (Grant No. RS2023-0859), Karolinska Institutet, Stockholm, Sweden, Department of Pediatrics, Örebro University, and Örebro University Hospital, Sweden.

Available from: 2025-06-25 Created: 2025-06-25 Last updated: 2025-06-25Bibliographically approved
Loid, P., Wang, F., Lennartsson, O., Muurinen, M., Costantini, A., Vats, S., . . . Mäkitie, O. (2025). Short stature, brachydactyly and joint contractures associated with novel FBN2 variants in two families. Journal of Medical Genetics, Article ID jmg-2024-110533.
Open this publication in new window or tab >>Short stature, brachydactyly and joint contractures associated with novel FBN2 variants in two families
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2025 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, article id jmg-2024-110533Article in journal (Refereed) Epub ahead of print
Abstract [en]

BACKGROUND: Fibrillinopathies comprise allelic disorders with opposing phenotypes. Pathogenic variants in fibrillin-2, encoded by FBN2, have mainly been associated with congenital contractural arachnodactyly but in a few cases also with brachydactyly.

METHODS AND RESULTS: We recruited two families with index patients presenting with short stature (heights ≤3 SD scores), brachydactyly, joint contractures and facial dysmorphism as major features. In Family 2, the proband and father also had carpal tunnel syndrome. Radiographs showed signs of mild skeletal dysplasia with short long bones, brachydactyly and mild metaphyseal and vertebral irregularity. Whole genome sequencing revealed novel variants in the FBN2 gene that segregated with the phenotype: in Family 1, a novel heterozygous missense variant c.4862G>A, p.(Cys1621Tyr) and in Family 2, a novel heterozygous deletion of exons 9-11. The missense variant affects a highly conserved residue and is predicted to be deleterious by most in silico tools. The FBN2 deletion affects a well-conserved region and leads to loss of the transforming growth factor β binding-like 2 domain and part of the calcium-binding epidermal growth factor-like domain.

CONCLUSION: Our findings suggest that short stature and mild skeletal dysplasia might be part of the spectrum of FBN2-related phenotypes. The study supports the role of FBN2 variants in growth failure and expands the molecular spectrum of FBN2 variants.

Place, publisher, year, edition, pages
BMJ Publishing Group Ltd, 2025
Keywords
Endocrinology, Genetic Testing, Human Genetics, Pediatrics
National Category
Medical Genetics and Genomics
Identifiers
urn:nbn:se:oru:diva-120520 (URN)10.1136/jmg-2024-110533 (DOI)001466929000001 ()40199564 (PubMedID)2-s2.0-105002599441 (Scopus ID)
Funder
Academy of FinlandSwedish Research CouncilSwedish Research Council, 2022- 00800Konung Gustaf V:s och Drottning Victorias FrimurarestiftelseRegion Stockholm, RS2020-0731Region Stockholm, 98866773377Edith och Erik Fernströms Stiftelse för medicinsk forskningStiftelsen SällsyntafondenSällskapet BarnavårdStiftelsen Frimurare Barnhuset i StockholmNyckelfondenÖrebro UniversityKarolinska Institute
Note

Funding Agencies:

This study was supported by Sigrid Jusélius Foundation, Novo Nordisk Foundation, Academy of Finland, Folkhälsan Research Foundation, Foundation for Paediatric Research, The Swedish Research Council (grant no. 2021-01807 and 2022-00800), Konung Gustaf V:s och Drottning Victorias Frimurarestiftelse, Stockholm County Council (grant no. RS2020-0731 and 98866773377), Finska Läkaresällskapet and Stiftelsen Dorothea Olivia, Karl Walter och Jarl Walter Perkléns minne, The Päivikki and Sakari Sohlberg Foundation, Erik and Edith Fernström Foundation for Medical Research, Stiftelsen Promobilia, Sällsynta Fonden, Sällskapet Barnavård, Stiftelsen Frimurare Barnhuset i Stockholm, Nyckelfonden, Örebro University and Karolinska Institutet, Stockholm, Sweden.

Available from: 2025-04-10 Created: 2025-04-10 Last updated: 2025-04-28Bibliographically approved
Ward, L. M., Högler, W., Glorieux, F. H., Portale, A. A., Whyte, M. P., Munns, C. F., . . . Imel, E. A. (2024). Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period. JBMR Plus, 8(1), Article ID ziad001.
Open this publication in new window or tab >>Burosumab vs conventional therapy in children with X-linked hypophosphatemia: results of the open-label, phase 3 extension period
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2024 (English)In: JBMR Plus, E-ISSN 2473-4039, Vol. 8, no 1, article id ziad001Article in journal (Refereed) Published
Abstract [en]

In a randomized, open-label phase 3 study of 61 children aged 1-12 years old with X-linked hypophosphatemia (XLH) previously treated with conventional therapy, changing to burosumab every 2 weeks (Q2W) for 64 weeks improved the phosphate metabolism, radiographic rickets, and growth compared with conventional therapy. In this open-label extension period (weeks 64-88), 21 children continued burosumab Q2W at the previous dose or crossed over from conventional therapy to burosumab starting at 0.8 mg/kg Q2W with continued clinical radiographic assessments through week 88. Efficacy endpoints and safety observations were summarized descriptively for both groups (burosumab continuation, n = 6; crossover, n = 15). At week 88 compared with baseline, improvements in the following outcomes were observed in the burosumab continuation and crossover groups, respectively: mean (SD) RGI-C rickets total score (primary outcome), +2.11 (0.27) and +1.89 (0.35); mean (SD) RGI-C lower limb deformity score, +1.61 (0.91) and +0.73 (0.82); and mean (SD) height Z-score + 0.41 (0.50) and +0.08 (0.34). Phosphate metabolism normalized rapidly in the crossover group and persisted in the continuation group. Mean (SD) serum alkaline phosphatase decreased from 169% (43%) of the upper limit of normal (ULN) at baseline to 126% (51%) at week 88 in the continuation group and from 157% (33%) of the ULN at baseline to 111% (23%) at week 88 in the crossover group. During the extension period, treatment-emergent adverse events (AEs) were reported in all 6 children in the burosumab continuation group and 14/15 children in the crossover group. The AE profiles in the randomized and extension periods were similar, with no new safety signals identified. Improvements from baseline in radiographic rickets continued in the extension period among children with XLH who remained on burosumab. Children who crossed over from conventional therapy to burosumab demonstrated a rapid improvement in phosphate metabolism and improved rickets healing over the ensuing 22 weeks.

Place, publisher, year, edition, pages
Oxford University Press, 2024
Keywords
burosumab, FGF23, phosphate, rare disease, x-linked hypophosphatemia
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-113457 (URN)10.1093/jbmrpl/ziad001 (DOI)001203133400006 ()38690124 (PubMedID)2-s2.0-85193424229 (Scopus ID)
Note

This study was sponsored and funded by Ultragenyx Pharmaceutical Inc. in partnership with Kyowa Kirin International plc. Medical writing support was provided by Ben Scott, PhD (Scott Medical Communications, LLC) and was funded by Ultragenyx Pharmaceutical Inc. Additional editorial support was provided by Jamie Ziobro, an employee and share holder of Ultragenyx Pharmaceutical Inc. At Indiana University, the research was done at the Indiana Clinical and Translational Sciences Institute, funded in part by UL1TR002529 from the National Institutes of Health, National Center for Advancing Translational Sciences, Clinical, and Translational Sciences Award. In Montreal and St. Louis, the work was also supported by the Shriners of North America. Dr. Ward is supported by a Tier 1 (Senior) Research Chair in Pediatric Bone Disorders from the University of Ottawa and Children's Hospital of Eastern Ontario Research Institute. 

Available from: 2024-04-30 Created: 2024-04-30 Last updated: 2025-01-20Bibliographically approved
Lodefalk, M., Lennartsson, O., Rodanaki, M., Cao, Y., Lodefalk, M. & Nilsson, O. (2024). Long-Term Health Outcomes of Delayed Puberty in Males: A Comprehensive Population-Based Study. Paper presented at 62nd Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2024), Liverpool, UK, November 16-18, 2024. Hormone Research in Paediatrics, 97(Suppl. 3), 97-97, Article ID RFC3.5.
Open this publication in new window or tab >>Long-Term Health Outcomes of Delayed Puberty in Males: A Comprehensive Population-Based Study
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2024 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 97, no Suppl. 3, p. 97-97, article id RFC3.5Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Introduction: Delayed puberty in boys, defined as lack of pubertal onset by the age of 14 years, is often constitutional and self-limited. However, it can lead to feelings of sadness and anxiety. The long-term health consequences of delayed puberty in males are not well understood.

Objective: To study the long-term morbidity in young men exposed to delayed puberty.

Methods: All Swedish men born between 1991 and 1993 who were diagnosed with delayed puberty at the ages of 14.0–17.9 years were identified in nation-wide registries. For each index person, 10 control individuals were randomly selected, matched for sex, year of birth, and county of residence. Swedish nation-wide registries were also used to determine outcomes, including inpatient and outpatient care, prescription of medications, and mortality. The outcomes were tracked annually from the age of 18 until the end of year 2022 (approximately 30 years of age).

Results: 1,245 men with delayed puberty and 12,450 control individuals were identified and included in the study. During the follow-up period, 32% of those with delayed puberty had at least one inpatient care occasion compared to 27% of those without delayed puberty (p < 0.001). Among those with at least one inpa-tient care occasion, men with delayed puberty had more inpatient stays compared to control individuals (median (25–75th percentile) 1 (1–3) vs. 1 (1–2), p = 0.016). A higher proportion of men with delayed puberty had a hospital-based outpatient visit compared to control individuals (90% vs. 86%, p < 0.001). The number of outpatient visits was higher in men with delayed puberty (6 (2–14) vs. 4 (1–10), p < 0.001). In addition, prescriptions of medications were provided more often to men with delayed puberty (16 (6–45) vs. 10 (4–25), p < 0.001). Ten men with delayed puberty and 95 control individuals died during the follow-up (0.80% vs. 0.76%, p = 0.879). Most deaths were due to injuries or intoxications. Among deceased men, those with delayed puberty were older when they died (27.5 years (26–29) vs. 24 years (21–26), p = 0.031).

Conclusion: Delayed puberty in boys is associated with a higher frequency of inpatient stays, outpatient visits, and prescription of medications in young adulthood. This indicates that male delayed puberty is not harmless, and careful follow-up of these patients is needed. Further investigations of the increased need of health care are warranted.

Place, publisher, year, edition, pages
S. Karger, 2024
National Category
Endocrinology and Diabetes Pediatrics
Identifiers
urn:nbn:se:oru:diva-118495 (URN)001366024300146 ()
Conference
62nd Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2024), Liverpool, UK, November 16-18, 2024
Available from: 2025-01-17 Created: 2025-01-17 Last updated: 2025-04-28Bibliographically approved
Sandvik, U., Ringvall, E., Klangemo, K., Hallgrimsdottir, S., Gkourogianni, A., Ottosson, L., . . . Nilsson, O. (2024). Management and outcomes of foramen magnum stenosis in children with achondroplasia at a single center over 15 years. Journal of Neurosurgery: Pediatrics, 34(5), 470-478
Open this publication in new window or tab >>Management and outcomes of foramen magnum stenosis in children with achondroplasia at a single center over 15 years
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2024 (English)In: Journal of Neurosurgery: Pediatrics, ISSN 1933-0707, E-ISSN 1933-0715, Vol. 34, no 5, p. 470-478Article in journal (Refereed) Published
Abstract [en]

OBJECTIVE: Achondroplasia is associated with foramen magnum stenosis (FMS), which can lead to sudden unexpected death in infants. There is no wide consensus regarding the best management of FMS. This study aimed to analyze the prevalence of FMS in a cohort of children with achondroplasia and to evaluate screening and neurosurgical interventions of FMS regarding its effects and complications.

METHODS: The authors conducted a retrospective cohort study including all children with achondroplasia assessed or treated at Karolinska University Hospital between September 2005 and June 2020. The severity of FMS was graded using the MRI Achondroplasia Foramen Magnum Score (AFMS). The AFMS was correlated with neurological examinations and polysomnography (PSG) results.

RESULTS: Severe FMS (AFMS 3-4) was present in 35% of the 51 children included in the study. As many as 65% of the children in the cohort underwent foramen magnum decompression (FMD). Neurological examination had a high specificity (94%) but a low sensitivity (28%) for severe FMS. Signs of central apnea on PSG did not correlate with severity of FMS (p = 0.735). Surgery improved FMS (p < 0.001) with a nonsignificant trend of decreased central apnea (p = 0.070), but carried a 9% risk of severe surgery- and anesthesia-related complications.

CONCLUSIONS: This study confirmed previous reports that severe FMS is common in children with achondroplasia, that neurological symptoms may be absent even in severe FMS, and that FMD improves FMS and may improve central apnea. The finding that neurological examination had a low sensitivity for severe FMS supports the recommendation that all children with achondroplasia should undergo early MRI.

Place, publisher, year, edition, pages
American Association of Neurological Surgeons, 2024
Keywords
achondroplasia, foramen magnum stenosis, foramen magnum decompression, surgical complications, magnetic resonance imaging, congenital
National Category
Pediatrics
Identifiers
urn:nbn:se:oru:diva-118527 (URN)10.3171/2024.6.PEDS23586 (DOI)001381996100006 ()39213664 (PubMedID)2-s2.0-85208449171 (Scopus ID)
Funder
Swedish Research Council, 2021-01807IngaBritt and Arne Lundberg’s Research FoundationRegion Stockholm, RS2020-0731Novo Nordisk Foundation, NNF16OC0021508Edith och Erik Fernströms Stiftelse för medicinsk forskningSällskapet BarnavårdStiftelsen Frimurare Barnhuset i StockholmNyckelfondenÖrebro UniversityKarolinska Institute
Note

This work was supported by grants from the Swedish Research Council (no. 2021-01807), IngaBritt och Arne Lundbergs forskningsstiftelse, the Stockholm County Council (no. RS2020-0731), Novo Nordisk Foundation (no. NNF16OC0021508), Erik and Edith Fernström Foundation for Medical Research, Promobilia, Sällsynta Fonden, Sällskapet Barnavård, Stiftelsen Frimurare Barnhuset i Stockholm, Nyckelfonden, Örebro University (Örebro, Sweden), and Karolinska Institutet (Stockholm, Sweden).

Available from: 2025-01-15 Created: 2025-01-15 Last updated: 2025-01-15Bibliographically approved
M. Boot, A., Ariceta, G., Beck-Nielsen, S. S., Brandi, M. L., Briot, K., Collantes, C. d., . . . Emma, F. (2024). Real-world non-interventional post-authorization safety study of long-term use of burosumab in children and adolescents with X-linked hypophosphatemia: first interim analysis. Therapeutic advances in chronic disease, 15, Article ID 20406223241247643.
Open this publication in new window or tab >>Real-world non-interventional post-authorization safety study of long-term use of burosumab in children and adolescents with X-linked hypophosphatemia: first interim analysis
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2024 (English)In: Therapeutic advances in chronic disease, E-ISSN 2040-6223, Vol. 15, article id 20406223241247643Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: X-linked hypophosphatemia (XLH) is a rare, progressive disorder characterized by excess fibroblast growth factor 23 (FGF23), causing renal phosphate-wasting and impaired active vitamin D synthesis. Burosumab is a recombinant human monoclonal antibody that inhibits FGF23, restoring patient serum phosphate levels. Safety data on long-term burosumab treatment are currently limited.

OBJECTIVES: This post-authorization safety study (PASS) aims to monitor long-term safety outcomes in children and adolescents (1-17 years) treated with burosumab for XLH. This first interim analysis reports the initial PASS safety outcomes.

DESIGN: A 10-year retrospective and prospective cohort study. METHODS: This PASS utilizes International XLH Registry (NCT03193476) data, which includes standard diagnostic and monitoring practice data at participating European centers.

RESULTS: At data cut-off (13 May 2021), 647 participants were included in the International XLH Registry; 367 were receiving burosumab, of which 67 provided consent to be included in the PASS. Mean (SD) follow-up time was 2.2 (1.0) years. Mean (SD) age was 7.3 (4.3) years (range 1.0-17.5 years). Mean duration of burosumab exposure was 29.7 (25.0) months. Overall, 25/67 participants (37.3%) experienced ⩾1 adverse event (AE) during follow-up; 83 AEs were reported. There were no deaths, no AEs leading to treatment withdrawal, nor serious AEs related to treatment. The most frequently reported AEs were classified as 'musculoskeletal and connective tissue disorders', with 'pain in extremity' most frequently reported, followed by 'infections and infestations', with 'tooth abscess' the most frequently reported.

CONCLUSION: In this first interim analysis of the PASS, covering the initial 2 years of data collection, the safety profile of burosumab is consistent with previously reported safety data. The PASS will provide long-term safety data over its 10-year duration for healthcare providers and participants with XLH that contribute to improvements in the knowledge of burosumab safety.

TRIAL REGISTRATION: European Union electronic Register of Post-Authorisation Studies: EUPAS32190.

Place, publisher, year, edition, pages
Sage Publications, 2024
Keywords
X-linked hypophosphatemia, burosumab, patient registry, post-authorization safety study, safety
National Category
Pediatrics
Identifiers
urn:nbn:se:oru:diva-113764 (URN)10.1177/20406223241247643 (DOI)001225645000001 ()38764445 (PubMedID)2-s2.0-85193572363 (Scopus ID)
Available from: 2024-05-22 Created: 2024-05-22 Last updated: 2024-05-29Bibliographically approved
Imel, E. A., Glorieux, F. H., Whyte, M. P., Portale, A. A., Munns, C. F., Nilsson, O., . . . Ward, L. M. (2023). Burosumab Versus Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Sub-group Analysis by Dose Level. Journal of Clinical Endocrinology and Metabolism, 108(11), 2990-2998
Open this publication in new window or tab >>Burosumab Versus Phosphate/Active Vitamin D in Pediatric X-Linked Hypophosphatemia: A Sub-group Analysis by Dose Level
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2023 (English)In: Journal of Clinical Endocrinology and Metabolism, ISSN 0021-972X, E-ISSN 1945-7197, Vol. 108, no 11, p. 2990-2998Article in journal (Refereed) Published
Abstract [en]

PURPOSE: In an open label, randomized, controlled, phase 3 trial in 61 children 1 to 12 years old with X-linked hypophosphatemia (XLH), burosumab improved rickets versus continuing conventional therapy with active vitamin D and phosphate. Here, we conducted an analysis to determine whether skeletal responses differed when switching to burosumab versus continuing higher or lower doses of conventional therapy.

METHODS: Conventional therapy dose groups were defined as: higher dose phosphate >40 mg/kg [HPi], lower dose phosphate ≤40 mg/kg [LPi], higher dose alfacalcidol >60 ng/kg or calcitriol >30 ng/kg [HD], and lower dose alfacalcidol ≤60 ng/kg or calcitriol ≤30 ng/kg [LD].

RESULTS: At Week 64, the Radiographic Global Impression of Change (RGI-C) for rickets was higher (better) in children randomized to burosumab versus conventional therapy for all pre-baseline dose groups: HPi (+1.72 versus +0.67), LPi (+2.14 versus +1.08), HD (+1.90 versus +0.94), LD (+2.11 versus +1.06). At Week 64, the RGI-C for rickets was also higher in children randomized to burosumab (+2.06) versus conventional therapy for all on-study dose groups: HPi (+1.03), LPi (+1.05), HD (+1.45), LD (+0.72). Serum alkaline phosphatase also decreased in the burosumab treated patients more than in the conventional therapy group, regardless of on-study phosphate and active vitamin D doses.

MAIN CONCLUSIONS: Prior phosphate or active vitamin D doses did not influence treatment response after switching to burosumab among children with XLH and active radiographic rickets. Switching from conventional therapy to burosumab improved rickets and serum alkaline phosphatase more than continuing either higher or lower doses of phosphate or active vitamin D.

Place, publisher, year, edition, pages
Oxford University Press, 2023
Keywords
FGF23, X-linked hypophosphatemia, XLH, active vitamin D, burosumab, oral phosphate, rickets
National Category
Pediatrics
Identifiers
urn:nbn:se:oru:diva-105679 (URN)10.1210/clinem/dgad230 (DOI)000994550900001 ()37084401 (PubMedID)2-s2.0-85175118781 (Scopus ID)
Available from: 2023-04-25 Created: 2023-04-25 Last updated: 2023-12-08Bibliographically approved
Kvist, O., Dorniok, T., Sanmartin Berglund, J., Nilsson, O., Flodmark, C.-E. & Diaz, S. (2023). DTI assessment of the maturing growth plate of the knee in adolescents and young adults. European Journal of Radiology, 162, Article ID 110759.
Open this publication in new window or tab >>DTI assessment of the maturing growth plate of the knee in adolescents and young adults
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2023 (English)In: European Journal of Radiology, ISSN 0720-048X, E-ISSN 1872-7727, Vol. 162, article id 110759Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To assess the growth plates of the knee in a healthy population of young adults and adolescents using DTI, and to correlate the findings with chronological age and skeletal maturation.

METHODS: A prospective, cross-sectional study to assess the tibial and femoral growth plates with DTI in 155 healthy volunteers aged between 14.0 and 21 years old. Echo-planar DTI with 15 directions and b value of 0 and 600 s/mm2 was performed on a 3 T whole-body scanner.

RESULTS: A relationship was observed between chronological age and most DTI metrics (fractional anisotropy, mean diffusivity, and radial diffusivity), tract length and volume. (No significant relationship could be seen for axonal diffusivity and tract length.) Subdivision according to skeletal maturation showed the greatest tract lengths and volumes seen in stage 4b and not 4a. The intra-observer agreement was significant (P = 0.01) for all the measured variables, but agreement varied (femur 0.53 - 0.98; tibia 0.58 - 0.98). Spearman's correlation showed a significant correlation for age (P = 0.05; P = 0.01) as well as for the fractional anisotropy value within all variables in both femur and tibia. Tract number and volume had a similar correlation with most variables, especially the DTI metrics, and would seem to be interchangeable.

CONCLUSION: The current study indicates that DTI metrics could be a tool to assess the skeletal maturation process of the growth plate and its activity. Tractography seems promising to assess the activity of the growth plate in a younger population but must be used with caution in the more mature growth plate.

Place, publisher, year, edition, pages
Elsevier, 2023
Keywords
Diffusion tensor imaging, Growth plate, Magnetic resonance imaging, Maturation process, Puberty
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:oru:diva-105101 (URN)10.1016/j.ejrad.2023.110759 (DOI)000954219700001 ()36931119 (PubMedID)2-s2.0-85150174214 (Scopus ID)
Available from: 2023-03-20 Created: 2023-03-20 Last updated: 2023-04-12Bibliographically approved
Bendre, A., Ottosson, L., Baroncelli, M., Dou, Z. & Nilsson, O. (2023). Growth failure in aggrecan haploinsufficiency is due to a decrease in growth plate matrix volume and hypertrophic cell size. Paper presented at 61st Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2023), The Hague, Netherlands, September 21-23, 2023. Hormone Research in Paediatrics, 96(Suppl. 4), 40-41, Article ID FC4.4.
Open this publication in new window or tab >>Growth failure in aggrecan haploinsufficiency is due to a decrease in growth plate matrix volume and hypertrophic cell size
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2023 (English)In: Hormone Research in Paediatrics, ISSN 1663-2818, E-ISSN 1663-2826, Vol. 96, no Suppl. 4, p. 40-41, article id FC4.4Article in journal, Meeting abstract (Other academic) Published
Abstract [en]

Background: Heterozygous loss-of-function mutations in the aggrecan gene (ACAN) cause autosomal dominant short stature with advanced bone age, early-onset osteoarthritis and intervertebral disc disease (SSOAOD; OMIM#165800). ACAN mutations is a relatively common finding in idiopathic short stature (ISS) and has been reported to be the cause of growth failure in approximately 2% of children with ISS. However, the underlying cellular and molecular mechanisms by which ACAN mutations cause growth failure in SSOAOD have not been elucidated.

Objective: To investigate the underlying cellular and molecular mechanisms of growth failure using a mouse model of SSOAOD.

Methods: Cartilage matrix deficiency mouse (Acan cmd) has a naturally occurring 7 bp micro-deletion in aggrecan gene. Heterozygous Acancmd and wild-type (WT) male and female mice were assessed for skeletal and body growth at 1,3,6,12 and 24 weeks of age. Histomorphometric analysis was performed on Masson-Trichrome stained proximal tibial and distal femoral growth plates. Cell proliferation was assessed by EdU incorporation. Quantification of percentage matrix area was performed using Image J. Single-cell RNA sequencing was carried out on chondro-cytes isolated from 18 day old WT and Acan cmd female mice according to 3’ gene expression protocol (10X Genomics).

Results: Heterozygous Acancmd mice were born at a normal size and similar to humans with SSOAOD but showed decreased postnatal growth resulting in a gradually worsening dwarfism with reduced total body length and tibial and femoral lengths (p<0.0001). In the growth plates, chondrocytes were found to be more tightly packed with reduced matrix area (p<0.0001) and increased column density in Acan cmd mice compared to WT mice. Growth plate height (p<0.0001), heights of the individual zones (p<0.001), the number of resting zone chondrocytes (p<0.01), proliferative cells per column (p<0.0001), and the size of terminal hypertrophic chondrocytes (p<0.001) were slightly reduced in both male and female Acan cmd mice, especially at 1 week of age. Interestingly, chondrocyte proliferation was similar in Acan cmd and WT mice at all time-points assessed (p=0.90). Female Acan cmd mice exhibited a more pronounced phenotype than male mice.

Conclusions: Similar to children with heterozygous ACAN mutations, heterozygous Acancmd mice exhibit a growth pattern with postnatal growth failure resulting in adult short stature. The growth failure is primarily caused by decreased matrix production and hypertrophic cell size, whereas chondrocyte proliferation is normal. Single-cell RNA sequencing of growth plate chondrocytes is ongoing and will identify the underlying pathogenic mechanisms and might also identify compensatory mechanisms limiting the effects of aggrecan haploinsufficiency.

Place, publisher, year, edition, pages
S. Karger, 2023
National Category
Pediatrics Endocrinology and Diabetes
Identifiers
urn:nbn:se:oru:diva-110875 (URN)001091262800049 ()
Conference
61st Annual Meeting of the European Society for Paediatric Endocrinology (ESPE 2023), The Hague, Netherlands, September 21-23, 2023
Available from: 2024-01-24 Created: 2024-01-24 Last updated: 2024-01-24Bibliographically approved
Kvist, O., Damberg, P., Dou, Z., Berglund, J. S., Flodmark, C.-E., Nilsson, O. & Diaz, S. (2023). Magnetic resonance and diffusion tensor imaging of the adolescent rabbit growth plate of the knee. Magnetic Resonance in Medicine, 89(1), 331-342
Open this publication in new window or tab >>Magnetic resonance and diffusion tensor imaging of the adolescent rabbit growth plate of the knee
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2023 (English)In: Magnetic Resonance in Medicine, ISSN 0740-3194, E-ISSN 1522-2594, Vol. 89, no 1, p. 331-342Article in journal (Refereed) Published
Abstract [en]

PURPOSE: To assess the ability of MRI-DTI to evaluate growth plate morphology and activity compared with that of histomorphometry and micro-CT in rabbits.

METHODS: The hind limbs of female rabbits aged 16, 20, and 24 wk (n = 4 per age group) were studied using a 9.4T MRI scanner with a multi-gradient echo 3D sequence and DTI in 14 directions (b-value = 984 s/mm2 ). After MRI, the right and left hind limb were processed for histological analysis and micro-CT, respectively. The Wilcoxon signed-rank test was used to evaluate the height and volume of the growth plate. Intraclass correlation and Pearson correlation coefficient were used to evaluate the association between DTI metrics and age.

RESULTS: The growth plate height and volume were similar for all modalities at each time point and age. Age was correlated with all tractography and DTI metrics in both the femur and tibia. A correlation was also observed between all the metrics at both sites. Tract number and volume declined with age; however, tract length did not show any changes. The fractional anisotropy color map showed lateral diffusion centrally in the growth plate and perpendicular diffusion in the hypertrophic zone, as verified by histology and micro-CT.

CONCLUSION: MRI-DTI may be useful for evaluating the growth plates.

Place, publisher, year, edition, pages
John Wiley & Sons, 2023
Keywords
Cartilage, diffusion-tensor imaging (DTI), growth plate, magnetic resonance imaging (MRI), skeletal maturation
National Category
Radiology, Nuclear Medicine and Medical Imaging
Identifiers
urn:nbn:se:oru:diva-101421 (URN)10.1002/mrm.29432 (DOI)000854034400001 ()36110062 (PubMedID)2-s2.0-85138045112 (Scopus ID)
Note

Funding agency:

Stockholm University Brain Imaging Centre

Available from: 2022-09-23 Created: 2022-09-23 Last updated: 2023-12-08Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-9986-8138

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