Juvenile Paget's disease in an Iranian kindred with vitamin D deficiency and novel homozygous TNFRSF11B mutation

Abstract

Juvenile Paget’s disease (JPD) is a rare heritable osteopathy characterized biochemically by markedly increased serum alkaline phosphatase (ALP) activity emanating from generalized acceleration of skeletal turnover. Affected infants and children typically suffer bone pain and fractures and deformities, become deaf, and have macrocranium. Some who survive to young adult life develop blindness from retinopathy engendered by vascular microcalcification. Most cases of JPD are caused by osteoprotegerin (OPG) deficiency due to homozygous loss-of-function mutations within the TNFRSF11B gene that encodes OPG. We report a 3-year-old Iranian girl with JPD and craniosynostosis who had vitamin D deficiency in infancy. She presented with fractures during the first year-of-life followed by bone deformities, delayed development, failure-to-thrive, and pneumonias. At 1 year-of-age, biochemical studies of serum revealed marked hyperphosphatasemia together with low-normal calcium and low inorganic phosphate and 25-hydroxyvitamin D levels. Several family members in previous generations of this consanguineous kindred may also have had JPD and vitamin D deficiency. Mutation analysis showed homozygosity for a unique missense change (c.130T>C, p.Cys44Arg) in TNFRSF11B that would compromise the cysteine-rich domain of OPG that binds receptor activator of NF-κB ligand (RANKL). Both parents were heterozygous for this mutation. The patient’s serum OPG level was extremely low and RANKL level markedly elevated. She responded well to rapid oral vitamin D repletion followed by pamidronate treatment given intravenously. Our patient is the first Iranian reported with JPD. Her novel mutation in TNFRSF11B plus vitamin D deficiency in infancy was associated with severe JPD uniquely complicated by craniosynostosis. Pamidronate treatment with vitamin D sufficiency can be effective treatment for the skeletal disease caused by the OPG deficiency form of JPD.

Juvenile Paget's disease with heterozygous duplication within TNFRSF11A encoding RANK

“…(11, 12) Subsequent publications, including several in which JPD patients were re-studied, (13, 16) typically revealed TNFRSF11B defects. (13, 38, 39, 51) Thus, JPD1 seems to be the most prevalent JPD. (4) However, we found here in our two unrelated JPD patients negative for TNFRSF11B (OPG) mutations, (11) no TNFRSF11A (RANK) or TNFSF11 (RANKL) defects.…”

A Higher Proportion of Craniosynostosis Genes Are Cancer Driver Genes

“…These 17 new genes found through this process were added to the CRS genes list: AXIN2 (Yilmaz et al, 2018), BBS9 (Justice et al, 2012; Sewda et al, 2019), BCOR (O’Byrne et al, 2017) (for Oculo-facio-cardio-dental syndrome, or microphthalmia syndrome), BGLAP (Sowińska-Seidler et al, 2018), COLEC10 (for 3MC syndrome) (Munye et al, 2017), FGFRL1 (Rieckmann et al, 2009) (for Antley-Bixler syndrome), GCK (for Greig cephalopolysyndactyly syndrome) (Zung et al, 2011), LMNA (Sowińska-Seidler et al, 2018), PPP3CA (Mizuguchi et al, 2018), PTH2R (Kim et al, 2015), RAF1 (for Noonan syndrome with multiple lentigines, or leopard syndrome) (Rodríguez et al, 2019), SIX2 (for frontonasal dysplasia syndrome) (Hufnagel et al, 2016), SMURF1, SPRY1, SPRY4 (Timberlake et al, 2016, 2017), TCOF1 (for Treacher Collins syndrome) (Horiuchi et al, 2004), TNFRSF11B (for Juvenile Paget disease) (Saki et al, 2013).…”

Contribution of acidic extracellular microenvironment of cancer-colonized bone to bone pain

“…The mutations in the signal peptide region of the RANK protein cause familial expansile osteolysis, a rare autosomal dominant disorder characterized by focal areas of enhanced bone resorption, and familial Paget s disease [15]. OPG deficiency due to homozygous loss-of-function mutations within the TNFRSF11B gene is a cause of Juvenile Paget's disease [16]. Thus, osteoclasts are evidently the principal causative player in diverse bone disorders.…”