Chronic idiopathic hyperphosphatasia: normalization of bone turnover with cyclical intravenous pamidronate therapy

Tau, Cristina; Mautalén, C.; Casco, C.; Àlvarez, Verònica; Rubinstein, Marta

doi:10.1016/j.bone.2004.03.013

Cited by 26 publications

(14 citation statements)

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“…(4) The skeletal disease may lead to conductive and sensorineural deafness, bone pain, fractures, and osteosarcoma. (4) Although described only briefly in case reports, (40–49) dental disease too seems common in JPD. (4) Normal teeth have been reported, (41) but more often there are missing incisors, (43, 44) resorbed (45) or loose teeth, loss of lamina dura, (14, 46) premature exfoliation of deciduous teeth, (44) or delayed eruption of the dentition.…”

Section: V) Discussionmentioning

confidence: 99%

“…(4) Normal teeth have been reported, (41) but more often there are missing incisors, (43, 44) resorbed (45) or loose teeth, loss of lamina dura, (14, 46) premature exfoliation of deciduous teeth, (44) or delayed eruption of the dentition. (47–49) Dental abnormalities also accompany the apparently distinctive but unexplained form of JPD associated with mental retardation. (40) However, only JPD1 among the mendelian disorders of RANKL/OPG/RANK signaling leads to VMC, (4) which resembles this complication of pseudoxanthoma elasticum (14) (OMIM #177850, #254800) (3) and generalized arterial calcification of infancy (50) (OMIM #208000, #614473).…”

Section: V) Discussionmentioning

confidence: 99%

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

Whyte

Tau

McAlister

et al. 2014

Bone

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Mendelian disorders of RANKL/OPG/RANK signaling feature the extremes of aberrant osteoclastogenesis and cause either osteopetrosis or rapid turnover skeletal disease. The patients with autosomal dominant accelerated bone remodeling have familial expansile osteolysis, early-onset Paget’s disease of bone, expansile skeletal hyperphosphatasia, or panostotic expansile bone disease due to heterozygous 18-, 27-, 15-, and 12-bp insertional duplications, respectively, within exon 1 of TNFRSF11A that encodes the signal peptide of RANK. Juvenile Paget’s disease (JPD), an autosomal recessive disorder, manifests extremely fast skeletal remodeling, and is usually caused by loss-of-function mutations within TNFRSF11B that encodes OPG. These disorders are ultra-rare. A 13-year-old Bolivian girl was referred at age 3 years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2 years involved missing ossicles and eroded cochleas. Teeth often had absorbed roots, broke, and were lost. Radiographs had revealed acquired tubular bone widening, cortical thickening, and coarse trabeculation. Biochemical markers indicated rapid skeletal turnover. Histopathology showed accelerated remodeling with abundant osteoclasts. JPD was diagnosed. Immobilization from a femur fracture caused severe hypercalcemia that responded rapidly to pamidronate treatment followed by bone turnover marker and radiographic improvement. No TNFRSF11B mutation was found. Instead, a unique heterozygous 15-bp insertional tandem duplication (87dup15) within exon 1 of TNFRSF11A predicted the same pentapeptide extension of RANK that causes expansile skeletal hyperphosphatasia (84dup15). Single nucleotide polymorphisms in TNFRSF11A and TNFRSF11B possibly impacted her phenotype. Our findings: i) reveal that JPD can be associated with an activating mutation within TNFRSF11A, ii) expand the range and overlap of phenotypes among the mendelian disorders of RANK activation, and iii) call for mutation analysis to improve diagnosis, prognostication, recurrence risk assessment, and perhaps treatment selection among the monogenic disorders of RANKL/OPG/RANK activation.

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Section: V) Discussionmentioning

confidence: 99%

Section: V) Discussionmentioning

confidence: 99%

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

Whyte

Tau

McAlister

et al. 2014

Bone

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“…She was able to safely begin the PMD infusions that have been helpful for JPD. (6) However, anti-resorptive treatment may now be necessary lifelong to control her skeletal disease. (5) Fortunately, she did not have deafness, and it will be important to know if her hearing will be preserved by anti-resorptive therapy to block the destruction of middle ear bones characteristic of OPG deficiency.…”

Section: V) Discussionmentioning

confidence: 99%

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

Saki

Karamizadeh

Nasirabadi

et al. 2013

Journal of Bone and Mineral Research

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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.

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“…No benefit or obvious harm was produced. Treatment with cyclical intravenous pamidronate induced remarkable clinical and radiographic improvement with normalization of bone markers of osteoblastic and osteoclastic activity, including bone alkaline phosphatase, urinary hydroxyproline, and urinary CrossLaps (10). Intensive bisphosphonate treatment showed suppression of bone turnover and a doubling of trabecular thickness, with no mineralization defect, and no osteopetrosis (11).…”

Section: Discussionmentioning

confidence: 99%

Chronic idiopathic hyperphosphatasia with unusual dental findings - A case report

Sreejan

Gopakumar²,

Babu³

2012

J Clin Exp Dent

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Chronic idiopathic hyperphosphatasia(CIH) or juvenile Paget disease is believed to be a distinct disease characterized by an increase in the serum alkaline phosphatase, cortical thickening and bowing of the long bones, especially the femora. It is a rare autosomal recessive bone disorder, with excessive bone resorption and bone formation. Skeletal malformations in the legs may cause problems in walking and may eventually result in short stature. The radiographic appearances include widening of the diaphyses, vertebral osteoporosis, acetabular protrusion, and thickening of the skull vault. Intensive bisphosphonate treatment prevented the development of deformity and disability but there is no published data on long-term efficacy. Bisphosphonate therapy showed suppression of bone turnover, doubling of trabecular thickness with no mineralization defect, and no osteopetrosis. We report a female of 21 years, a case of chronic idiopathic hyperphosphatasia congenital form, with a history of fracture, short stature and malformed teeth. She had a waddling gait, bone deformities, kyphoscoliosis and curvature of her limbs. Key words:Hyperphosphatasia, autosomal recessive, alkaline phosphatase, short stature, cortical thickening, enamel hypoplasia.

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Chronic idiopathic hyperphosphatasia: normalization of bone turnover with cyclical intravenous pamidronate therapy

Cited by 26 publications

References 26 publications

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

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

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

Chronic idiopathic hyperphosphatasia with unusual dental findings - A case report

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