Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7).
Bone. 2020 Aug; 137:115364.BONE

Abstract

Juvenile Paget's disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphatasemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos. Soon after, other bi-allelic loss-of-function TNFRSF11B defects were identified in JPD worldwide. OPG inhibits osteoclastogenesis and osteoclast activity by decoying receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) away from its receptor RANK. Then, in 2014, we reported JPD in a Bolivian girl caused by a heterozygous activating duplication within TNFRSF11A encoding RANK. Herein, we identify mutation of a third gene underlying JPD. An infant girl began atraumatic fracturing of her lower extremity long-bones. Skull deformity and mild hearing loss followed. Our single investigation of the patient, when she was 15 years-of-age, showed generalized osteosclerosis and hyperostosis. DXA revealed a Z-score of +5.1 at her lumbar spine and T-score of +3.3 at her non-dominant wrist. Biochemical studies were consistent with positive mineral balance and several markers of bone turnover were elevated and included striking hyperphosphatasemia. Iliac crest histopathology was consistent with rapid skeletal remodeling. Measles virus transcripts, common in classic Paget's disease of bone, were not detected in circulating mononuclear cells. Then, reportedly, she responded to several months of alendronate therapy with less skeletal pain and correction of hyperphosphatasemia but had been lost to our follow-up. After we detected no defect in TNFRSF11A or B, trio exome sequencing revealed a de novo heterozygous missense mutation (c.926C>G; p.S309W) within SP7 encoding the osteoblast transcription factor osterix (specificity protein 7, transcription factor SP7). Thus, mutation of SP7 represents a third genetic cause of JPD.

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Authors+Show Affiliations

Whyte MP

Center For Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA; Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: mwhyte@shrinenet.org.

Campeau PM

Department of Pediatrics, University of Montreal, Montreal, Quebec H3T 1C5, Canada. Electronic address: p.campeau@umontreal.ca.

McAlister WH

Mallinckrodt Institute of Radiology, Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO 63110, USA. Electronic address: mcalisterw@wustl.edu.

Roodman GD

Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: groodman@iupui.edu.

Kurihara N

Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address: norikuri@iu.edu.

Nenninger A

Center For Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA. Electronic address: anenninger@shrinenet.org.

Duan S

Division of Bone and Mineral Diseases, Department of Internal Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address: sduan@wustl.edu.

Gottesman GS

Center For Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA. Electronic address: ggottesman@shrinenet.org.

Bijanki VN

Center For Metabolic Bone Disease and Molecular Research, Shriners Hospitals for Children - St. Louis, St. Louis, MO 63110, USA. Electronic address: vbijanki@shrinenet.org.

Sedighi H

Department of Plastic Surgery, Washington University School of Medicine at St. Louis Children's Hospital, St. Louis, MO 63110, USA.

Veis DJ

Mumm S

MeSH

Child, PreschoolFemaleHomozygoteHumansMutationOsteitis DeformansOsteoprotegerinRANK LigandSequence DeletionSp7 Transcription FactorTranscription FactorsYoung Adult

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32298837

Citation

Whyte, Michael P., et al. "Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7)." Bone, vol. 137, 2020, p. 115364.

Whyte MP, Campeau PM, McAlister WH, et al. Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7). Bone. 2020;137:115364.

Whyte, M. P., Campeau, P. M., McAlister, W. H., Roodman, G. D., Kurihara, N., Nenninger, A., Duan, S., Gottesman, G. S., Bijanki, V. N., Sedighi, H., Veis, D. J., & Mumm, S. (2020). Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7). Bone, 137, 115364. https://doi.org/10.1016/j.bone.2020.115364

Whyte MP, et al. Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7). Bone. 2020;137:115364. PubMed PMID: 32298837.

* Article titles in AMA citation format should be in sentence-case

TY - JOUR T1 - Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7). AU - Whyte,Michael P, AU - Campeau,Philippe M, AU - McAlister,William H, AU - Roodman,G David, AU - Kurihara,Nori, AU - Nenninger,Angela, AU - Duan,Shenghui, AU - Gottesman,Gary S, AU - Bijanki,Vinieth N, AU - Sedighi,Homer, AU - Veis,Deborah J, AU - Mumm,Steven, Y1 - 2020/04/13/ PY - 2020/02/04/received PY - 2020/04/09/revised PY - 2020/04/12/accepted PY - 2020/4/17/pubmed PY - 2021/6/22/medline PY - 2020/4/17/entrez KW - Alkaline phosphatase KW - Bone remodeling KW - Dental pathology KW - Dento-osseous disease KW - Fractures KW - Hyperostosis KW - Hyperphosphatasemia KW - Measles virus KW - Osteoblast KW - Osteoclast KW - Osteoprotegerin KW - Osteosclerosis KW - Osterix KW - Paget bone disease KW - Woven bone SP - 115364 EP - 115364 JF - Bone JO - Bone VL - 137 N2 - Juvenile Paget's disease (JPD) became in 1974 the commonly used name for ultra-rare heritable occurrences of rapid bone remodeling throughout of the skeleton that present in infancy or early childhood as fractures and deformity hallmarked biochemically by marked elevation of serum alkaline phosphatase (ALP) activity (hyperphosphatasemia). Untreated, JPD can kill during childhood or young adult life. In 2002, we reported that homozygous deletion of the gene called tumor necrosis factor receptor superfamily, member 11B (TNFRSF11B) encoding osteoprotegerin (OPG) explained JPD in Navajos. Soon after, other bi-allelic loss-of-function TNFRSF11B defects were identified in JPD worldwide. OPG inhibits osteoclastogenesis and osteoclast activity by decoying receptor activator of nuclear factor κ-B (RANK) ligand (RANKL) away from its receptor RANK. Then, in 2014, we reported JPD in a Bolivian girl caused by a heterozygous activating duplication within TNFRSF11A encoding RANK. Herein, we identify mutation of a third gene underlying JPD. An infant girl began atraumatic fracturing of her lower extremity long-bones. Skull deformity and mild hearing loss followed. Our single investigation of the patient, when she was 15 years-of-age, showed generalized osteosclerosis and hyperostosis. DXA revealed a Z-score of +5.1 at her lumbar spine and T-score of +3.3 at her non-dominant wrist. Biochemical studies were consistent with positive mineral balance and several markers of bone turnover were elevated and included striking hyperphosphatasemia. Iliac crest histopathology was consistent with rapid skeletal remodeling. Measles virus transcripts, common in classic Paget's disease of bone, were not detected in circulating mononuclear cells. Then, reportedly, she responded to several months of alendronate therapy with less skeletal pain and correction of hyperphosphatasemia but had been lost to our follow-up. After we detected no defect in TNFRSF11A or B, trio exome sequencing revealed a de novo heterozygous missense mutation (c.926C>G; p.S309W) within SP7 encoding the osteoblast transcription factor osterix (specificity protein 7, transcription factor SP7). Thus, mutation of SP7 represents a third genetic cause of JPD. SN - 1873-2763 UR - https://www.unboundmedicine.com/medline/citation/32298837/Juvenile_Paget DB - PRIME DP - Unbound Medicine ER -

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Juvenile Paget's Disease From Heterozygous Mutation of SP7 Encoding Osterix (Specificity Protein 7, Transcription Factor SP7).Bone. 2020 Aug; 137:115364.BONE