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X-linked osteoporosis with fractures

MedGen UID:
1674557
•Concept ID:
C5190610
•
Disease or Syndrome
SNOMED CT: X-linked osteoporosis with fractures (782785002)
Modes of inheritance:
X-linked recessive inheritance
MedGen UID:
375779
•Concept ID:
C1845977
•
Finding
Source: Orphanet
A mode of inheritance that is observed for recessive traits related to a gene encoded on the X chromosome. In the context of medical genetics, X-linked recessive disorders manifest in males (who have one copy of the X chromosome and are thus hemizygotes), but generally not in female heterozygotes who have one mutant and one normal allele.
See: This record
X-linked recessive inheritance (Orphanet)
 
Monarch Initiative: MONDO:0018315
Orphanet: ORPHA391330

Definition

A rare genetic primary bone dysplasia with decreased bone density disorder with characteristics of childhood-onset osteoporosis associated with recurrent, multiple, osteoporotic, long bone fractures and/or vertebral compression fractures, significant height loss in adulthood, low bone mineral density scores and otherwise no other abnormalities. Heterozygote females may be unaffected or have a milder phenotype. There is evidence the disease can be caused by mutation in the PLS3 gene on chromosome Xq23. [from SNOMEDCT_US]

Professional guidelines

PubMed

Chapter 4: Differential diagnosis of primary hyperparathyroidism.
Kamenický P, Houillier P, Vantyghem MC
Ann Endocrinol (Paris) 2025 Feb;86(1):101693. Epub 2025 Jan 14 doi: 10.1016/j.ando.2025.101693. PMID: 39818292
Proceedings of the 2023 Santa Fe Bone Symposium: Progress and Controversies in the Management of Patients with Skeletal Diseases.
Lewiecki EM, Bellido T, Bilezikian JP, Brown JP, Farooki A, Kovacs CS, Lee B, Leslie WD, McClung MR, Prasarn ML, Sellmeyer DE
J Clin Densitom 2023 Oct-Dec;26(4):101432. Epub 2023 Oct 14 doi: 10.1016/j.jocd.2023.101432. PMID: 37944445Free PMC Article
Pathogenesis and treatment of osteoporosis in patients with hemophilia.
Lin X, Gao P, Zhang Q, Jiang Y, Wang O, Xia W, Li M
Arch Osteoporos 2023 Jan 4;18(1):17. doi: 10.1007/s11657-022-01203-9. PMID: 36598583Free PMC Article

Recent clinical studies

Etiology

The Management of Bone Defects in Rett Syndrome.
Caffarelli C, Gonnelli S
Calcif Tissue Int 2025 Jan 3;116(1):11. doi: 10.1007/s00223-024-01322-0. PMID: 39751871
Bone fragility and osteoporosis in children and young adults.
Formosa MM, Christou MA, Mäkitie O
J Endocrinol Invest 2024 Feb;47(2):285-298. Epub 2023 Sep 5 doi: 10.1007/s40618-023-02179-0. PMID: 37668887Free PMC Article
Pathogenesis and treatment of osteoporosis in patients with hemophilia.
Lin X, Gao P, Zhang Q, Jiang Y, Wang O, Xia W, Li M
Arch Osteoporos 2023 Jan 4;18(1):17. doi: 10.1007/s11657-022-01203-9. PMID: 36598583Free PMC Article
Familial exudative vitreoretinopathy and related retinopathies.
Gilmour DF
Eye (Lond) 2015 Jan;29(1):1-14. Epub 2014 Oct 17 doi: 10.1038/eye.2014.70. PMID: 25323851Free PMC Article
What is new in genetics and osteogenesis imperfecta classification?
Valadares ER, Carneiro TB, Santos PM, Oliveira AC, Zabel B
J Pediatr (Rio J) 2014 Nov-Dec;90(6):536-41. Epub 2014 Jul 18 doi: 10.1016/j.jped.2014.05.003. PMID: 25046257

Diagnosis

Chapter 4: Differential diagnosis of primary hyperparathyroidism.
Kamenický P, Houillier P, Vantyghem MC
Ann Endocrinol (Paris) 2025 Feb;86(1):101693. Epub 2025 Jan 14 doi: 10.1016/j.ando.2025.101693. PMID: 39818292
The Management of Bone Defects in Rett Syndrome.
Caffarelli C, Gonnelli S
Calcif Tissue Int 2025 Jan 3;116(1):11. doi: 10.1007/s00223-024-01322-0. PMID: 39751871
PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families.
Costa A, Martins A, Machado C, Lundberg E, Nilsson O, Wang F, Costantini A, Tournis S, Höppner J, Grasemann C, Mäkitie O
Calcif Tissue Int 2024 Feb;114(2):157-170. Epub 2023 Dec 3 doi: 10.1007/s00223-023-01162-4. PMID: 38043102Free PMC Article
Bone fragility and osteoporosis in children and young adults.
Formosa MM, Christou MA, Mäkitie O
J Endocrinol Invest 2024 Feb;47(2):285-298. Epub 2023 Sep 5 doi: 10.1007/s40618-023-02179-0. PMID: 37668887Free PMC Article
Mendelian bone fragility disorders.
Robinson ME, Rauch F
Bone 2019 Sep;126:11-17. Epub 2019 Apr 27 doi: 10.1016/j.bone.2019.04.021. PMID: 31039433

Therapy

PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families.
Costa A, Martins A, Machado C, Lundberg E, Nilsson O, Wang F, Costantini A, Tournis S, Höppner J, Grasemann C, Mäkitie O
Calcif Tissue Int 2024 Feb;114(2):157-170. Epub 2023 Dec 3 doi: 10.1007/s00223-023-01162-4. PMID: 38043102Free PMC Article
Pathogenesis and treatment of osteoporosis in patients with hemophilia.
Lin X, Gao P, Zhang Q, Jiang Y, Wang O, Xia W, Li M
Arch Osteoporos 2023 Jan 4;18(1):17. doi: 10.1007/s11657-022-01203-9. PMID: 36598583Free PMC Article
Case report: Clinical characteristics and treatment of secondary osteoporosis induced by X-linked congenital adrenal dysplasia.
Tao X, Xu T, Liu L, Lin X, Zhang Z, Yue H
Front Endocrinol (Lausanne) 2022;13:961322. Epub 2022 Dec 8 doi: 10.3389/fendo.2022.961322. PMID: 36568103Free PMC Article
Identification of a novel splicing mutation and genotype-phenotype correlations in rare PLS3-related childhood-onset osteoporosis.
Wu Z, Feng Z, Zhu X, Dai Z, Min K, Qiu Y, Yi L, Xu L, Zhu Z
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Effects of Bisphosphonates on Osteoporosis Induced by Duchenne Muscular Dystrophy: A Prospective Study.
Zheng WB, Dai Y, Hu J, Zhao DC, Wang O, Jiang Y, Xia WB, Xing XP, Li M
Endocr Pract 2020 Dec;26(12):1477-1485. doi: 10.4158/EP-2020-0073. PMID: 33471740

Prognosis

Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.
Zervou Z, Bevers MSAM, Wyers CE, Bruggenwirth HT, Demirdas S, van den Bergh JP, Zillikens MC
J Bone Miner Res 2025 Feb 2;40(2):241-250. doi: 10.1093/jbmr/zjae186. PMID: 39658012
PLS3 Mutations in X-Linked Osteoporosis: Clinical and Genetic Features in Five New Families.
Costa A, Martins A, Machado C, Lundberg E, Nilsson O, Wang F, Costantini A, Tournis S, Höppner J, Grasemann C, Mäkitie O
Calcif Tissue Int 2024 Feb;114(2):157-170. Epub 2023 Dec 3 doi: 10.1007/s00223-023-01162-4. PMID: 38043102Free PMC Article
Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders.
Oheim R, Tsourdi E, Seefried L, Beller G, Schubach M, Vettorazzi E, Stürznickel J, Rolvien T, Ehmke N, Delsmann A, Genest F, Krüger U, Zemojtel T, Barvencik F, Schinke T, Jakob F, Hofbauer LC, Mundlos S, Kornak U
J Clin Endocrinol Metab 2022 Jun 16;107(7):e3048-e3057. doi: 10.1210/clinem/dgac147. PMID: 35276006Free PMC Article
A novel nonsense variant in PLS3 causes X-linked osteoporosis in a Chinese family.
Wang L, Bian X, Cheng G, Zhao P, Xiang X, Tian W, Li T, Zhai Q
Ann Hum Genet 2020 Jan;84(1):92-96. Epub 2019 Jul 26 doi: 10.1111/ahg.12344. PMID: 31347706
A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.
Laine CM, Wessman M, Toiviainen-Salo S, Kaunisto MA, Mäyränpää MK, Laine T, Pekkinen M, Kröger H, Välimäki VV, Välimäki MJ, Lehesjoki AE, Mäkitie O
J Bone Miner Res 2015 Mar;30(3):510-8. doi: 10.1002/jbmr.2355. PMID: 25209159

Clinical prediction guides

The Management of Bone Defects in Rett Syndrome.
Caffarelli C, Gonnelli S
Calcif Tissue Int 2025 Jan 3;116(1):11. doi: 10.1007/s00223-024-01322-0. PMID: 39751871
Bone microarchitecture and strength in men and women with PLS3 gene variants assessed with HR-pQCT.
Zervou Z, Bevers MSAM, Wyers CE, Bruggenwirth HT, Demirdas S, van den Bergh JP, Zillikens MC
J Bone Miner Res 2025 Feb 2;40(2):241-250. doi: 10.1093/jbmr/zjae186. PMID: 39658012
Bone fragility and osteoporosis in children and young adults.
Formosa MM, Christou MA, Mäkitie O
J Endocrinol Invest 2024 Feb;47(2):285-298. Epub 2023 Sep 5 doi: 10.1007/s40618-023-02179-0. PMID: 37668887Free PMC Article
Genetic Diagnostics in Routine Osteological Assessment of Adult Low Bone Mass Disorders.
Oheim R, Tsourdi E, Seefried L, Beller G, Schubach M, Vettorazzi E, Stürznickel J, Rolvien T, Ehmke N, Delsmann A, Genest F, Krüger U, Zemojtel T, Barvencik F, Schinke T, Jakob F, Hofbauer LC, Mundlos S, Kornak U
J Clin Endocrinol Metab 2022 Jun 16;107(7):e3048-e3057. doi: 10.1210/clinem/dgac147. PMID: 35276006Free PMC Article
A novel nonsense variant in PLS3 causes X-linked osteoporosis in a Chinese family.
Wang L, Bian X, Cheng G, Zhao P, Xiang X, Tian W, Li T, Zhai Q
Ann Hum Genet 2020 Jan;84(1):92-96. Epub 2019 Jul 26 doi: 10.1111/ahg.12344. PMID: 31347706

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