Rare Inherited forms of Paget’s Disease and Related Syndromes

Abstract

Several rare inherited disorders have been described that show phenotypic overlap with Paget's disease of bone (PDB) and in which PDB is a component of a multisystem disorder affecting muscle and the central nervous system. These conditions are the subject of this review article. Insertion mutations within exon 1 of the TNFRSF11A gene, encoding the Receptor Activator of Nuclear Factor Kappa B (RANK) cause severe, PDB-like disorders including Familial Expansile Osteolysis, Early-onset familial PDB and Expansile Skeletal Flyperphosphatasia. The mutations interfere with normal processing of RANK and cause osteoclast activation through activation of nuclear factor kappa B (NFκB) independent of RANK Ligand stimulation. Recessive, loss of function mutations in the TNFRSF11B gene, which encodes osteoprotegerin, cause juvenile PDB and here the bone disease is due to unopposed activation of RANK by RANKL. Multisystem proteinopathy is a disorder characterised by myopathy and neurodegeneration in which PDB is often an integral component. It may be caused by mutations in several genes including VCP, HNRNPA1, HNRNPA2B1, SQSTM1, MATR3, and TIA1, some of which are involved in classical PDB. The mechanisms of osteoclast activation in these conditions is less clear but may involve NFκB activation through sequestration of IκB. The evidence base for management of these disorders is somewhat limited due to the fact they are extremely rare. Bisphosphonates have been successfully used to gain control of elevated bone remodeling but as yet, no effective treatment exists for the treatment of the muscle and neurological manifestations of MSP syndromes.

Pattern of SQSTM1 Gene Variants in a Hungarian Cohort of Paget’s Disease of Bone

“…According to the original article by Visconti MR et al, the overall frequency of alterations is on average 0.07% among unaffected controls [ 27 ] and, consistently, the allele frequency of p.Pro392Leu in the EXaC database has been reported to be 0.10%. In this regard it is interesting to note that some patients with pathogenic variants in SQSTM1 do not develop PDB but instead present with neurological disease such as amyotrophic lateral sclerosis (ALS) as part of multisystem proteinopathy syndromes [ 28 ] The reason underlying these different presentations remains incompletely understood but there is evidence that digenic inheritance of more than one variant may play a role [ 29 ].…”

A New Gene for Susceptibility to Paget's Disease of Bone and for Multisystem Proteinopathy

“…An intriguing observation that was overlooked by the authors is that PFN1 joins the growing list of genes in which mutations can either cause PDB or other phenotypes such as myopathy, amyotrophic lateral sclerosis, dementia, and Parkinson's disease ( 6–11 ) (Table 1). {TBL 1} The term multisystem proteinopathy (MSP) has been coined to refer to these syndromes.…”

“…( 9 ) They are characterized by accumulation of abnormal protein aggregates within cells, either because the disease‐causing mutations result in defects of protein degradation through the proteasome or because they act directly to increase the propensity of the mutated protein to form aggregates. ( 6,10 ) It has been known for many years that PFN1 mutations can cause ALS and when the causal mutations from these patients are expressed in vitro , insoluble protein aggregates are formed. ( 11 ) Because the truncating mutation described by Scotto di Carlo and colleagues seems to do the same when proteasomal degradation is inhibited by MG163, it looks as though PFN1 might be a candidate for a new form of MSP, which I provisionally have named MSP7.…”

Zoledronate in the prevention of Paget’s (ZiPP): protocol for a randomised trial of genetic testing and targeted zoledronic acid therapy to preventSQSTM1-mediated Paget’s disease of bone

“…Genetic factors play an important role in PDB. Many genetic variants have been identified that predispose to PDB and related syndromes1 2 but mutations in sequestosome-1 ( SQSTM1 ) are the most important predisposing factor, occurring in up to 50% of patients with a family history of PDB and up to 10% of people who are unaware of having a family history 3–8. Carriers of SQSTM1 mutations have more severe disease with an earlier age at onset than patients who do not carry mutations 9.…”