Michael P Whyte

Shriners Hospitals for Children, Tampa, Florida, United States

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Publications (266)2032.67 Total impact

  • José Luis Millán · Michael P. Whyte ·
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    ABSTRACT: Hypophosphatasia (HPP) results from ALPL mutations leading to deficient activity of the tissue-non-specific alkaline phosphatase isozyme (TNAP) and thereby extracellular accumulation of inorganic pyrophosphate (PPi), a natural substrate of TNAP and potent inhibitor of mineralization. Thus, HPP features rickets or osteomalacia and hypomineralization of teeth. Enzyme replacement using mineral-targeted TNAP from birth prevented severe HPP in TNAP-knockout mice and was then shown to rescue and substantially treat infants and young children with life-threatening HPP. Clinical trials are revealing aspects of HPP pathophysiology not yet fully understood, such as craniosynostosis and muscle weakness when HPP is severe. New treatment approaches are under development to improve patient care.
    Calcified Tissue International 11/2015; DOI:10.1007/s00223-015-0079-1 · 3.27 Impact Factor
  • Angela Rogers · Caroline Gorvin · Michael Whyte · Rajesh Thakker ·

    10/2015; DOI:10.1530/endoabs.38.P1

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    ABSTRACT: Heritable disorders that feature high bone mass (HBM) are rare. The etiology is typically a mutation(s) within a gene that regulates the differentiation and function of osteoblasts (OBs) or osteoclasts (OCs). Nevertheless, the molecular basis is unknown for approximately one-fifth of such entities. NF-κB signaling is a key regulator of bone remodeling and acts by enhancing OC survival while impairing OB maturation and function. The NF-κB transcription complex comprises five subunits. In mice, deletion of the p50 and p52 subunits together causes osteopetrosis (OPT). In humans, however, mutations within the genes that encode the NF-κB complex, including the Rela/p65 subunit, have not been reported. We describe a neonate who died suddenly and unexpectedly and was found at post-mortem to have HBM documented radiographically and by skeletal histopathology. Serum was not available for study. Radiographic changes resembled malignant OPT, but histopathological investigation showed morphologically normal OCs and evidence of intact bone resorption excluding OPT. Furthermore, mutation analysis was negative for eight genes associated with OPT or HBM. Instead, accelerated bone formation appeared to account for the HBM. Subsequently, trio-based whole exome sequencing revealed a heterozygous, de novo, missense mutation (c.1534_1535delinsAG, p.Asp512Ser) in exon 11 of RELA encoding Rela/p65. The mutation was then verified using bi-directional Sanger sequencing. Lipopolysaccharide stimulation of patient fibroblasts elicited impaired NF-κB responses compared to healthy control fibroblasts. Five unrelated patients with unexplained HBM did not show a RELA defect. Ours is apparently the first report of a mutation within the NF-κB complex in humans. The missense change is associated with neonatal osteosclerosis from in utero increased OB function rather than failed OC action. These findings demonstrate the importance of the Rela/p65 subunit within the NF-κB pathway for human skeletal homeostasis, and represent a new genetic cause of HBM. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 07/2015; DOI:10.1002/jbmr.2590 · 6.83 Impact Factor
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    ABSTRACT: The adaptor protein-2 sigma subunit (AP2σ2) is pivotal for clathrin-mediated endocytosis of plasma membrane constituents such as the calcium-sensing receptor (CaSR). Mutations of the AP2σ2 Arg15 residue result in familial hypocalciuric hypercalcaemia type 3 (FHH3), a disorder of extracellular calcium (Ca(2+) o) homeostasis. To elucidate the role of AP2σ2 in Ca(2+) o regulation, we investigated 65 FHH probands, without other FHH-associated mutations, for AP2σ2 mutations, characterized their functional consequences, and investigated the genetic mechanisms leading to FHH3. AP2σ2 mutations were identified in 17 probands, comprising five Arg15Cys, four Arg15His and eight Arg15Leu mutations. A genotype-phenotype correlation was observed with the Arg15Leu mutation leading to marked hypercalcaemia. FHH3 probands harboured additional phenotypes such as cognitive dysfunction. All three FHH3-causing AP2σ2 mutations impaired CaSR signal transduction in a dominant-negative manner. Mutational bias was observed at the AP2σ2 Arg15 residue as other predicted missense substitutions (Arg15Gly, Arg15Pro and Arg15Ser), which also caused CaSR loss-of-function, were not detected in FHH probands, and these mutations were found to reduce the numbers of CaSR-expressing cells. FHH3 probands had significantly greater serum calcium (sCa) and magnesium (sMg) concentrations with reduced urinary calcium to creatinine clearance ratios (CCCR) in comparison to FHH1 probands with CaSR mutations, and a calculated index of sCa*sMg/100*CCCR, that was≥5.0 had a diagnostic sensitivity and specificity of 83% and 86%, respectively, for FHH3. Thus, our studies demonstrate AP2σ2 mutations to result in a more severe FHH phenotype with genotype-phenotype correlations, and a dominant-negative mechanism of action with mutational bias at the Arg15 residue. © The Author 2015. Published by Oxford University Press.
    Human Molecular Genetics 06/2015; 24(18). DOI:10.1093/hmg/ddv226 · 6.39 Impact Factor

  • 06/2015; DOI:10.1530/boneabs.4.P97
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    ABSTRACT: To assess factors influencing the success of whole-genome sequencing for mainstream clinical diagnosis, we sequenced 217 individuals from 156 independent cases or families across a broad spectrum of disorders in whom previous screening had identified no pathogenic variants. We quantified the number of candidate variants identified using different strategies for variant calling, filtering, annotation and prioritization. We found that jointly calling variants across samples, filtering against both local and external databases, deploying multiple annotation tools and using familial transmission above biological plausibility contributed to accuracy. Overall, we identified disease-causing variants in 21% of cases, with the proportion increasing to 34% (23/68) for mendelian disorders and 57% (8/14) in family trios. We also discovered 32 potentially clinically actionable variants in 18 genes unrelated to the referral disorder, although only 4 were ultimately considered reportable. Our results demonstrate the value of genome sequencing for routine clinical diagnosis but also highlight many outstanding challenges.
    Nature Genetics 05/2015; 47(7). DOI:10.1038/ng.3304 · 29.35 Impact Factor
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    ABSTRACT: Hypophosphatasia (HPP) is caused by loss-of-function mutation(s) within the gene TNSALP that encodes the “tissue-nonspecific” isoenzyme of alkaline phosphatase (TNSALP). In HPP, inorganic pyrophosphate, an inhibitor of mineralization and substrate for TNSALP, accumulates extracellularly often leading to rickets or osteomalacia and tooth loss, and sometimes to craniosynostosis and calcium crystal arthropathies. HPP's remarkably broad-ranging expressivity spans stillbirth from profound skeletal hypomineralization to adult-onset dental problems or arthropathies without bone disease, which is largely explained by autosomal recessive versus autosomal dominant transmission from among several hundred, usually missense, TNSALP mutations. For clinical purposes, this expressivity has been codified according to absence or presence of skeletal disease and then patient age at presentation and diagnosis. Pediatric patients are reported principally with “odonto”, “childhood”, “infantile”, or “perinatal” HPP. However, this nosology has not been tested using a cohort of patients, and the ranges of the clinical and laboratory findings have not been defined and contrasted among these patient groups.
    Bone 02/2015; 75. DOI:10.1016/j.bone.2015.02.022 · 3.97 Impact Factor
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    ABSTRACT: Mutations in ALPL result in hypophosphatasia (HPP), a disease causing defective skeletal mineralization. ALPL encodes tissue nonspecific alkaline phosphatase (ALP), an enzyme that promotes mineralization by reducing inorganic pyrophosphate, a mineralization inhibitor. In addition to skeletal defects, HPP causes dental defects, and a mild clinical form of HPP, odontohypophosphatasia, features only a dental phenotype. The Alpl knockout (Alpl(-/-)) mouse phenocopies severe infantile HPP, including profound skeletal and dental defects. However, the severity of disease in Alpl(-/-) mice prevents analysis at advanced ages, including studies to target rescue of dental tissues. We aimed to generate a knock-in mouse model of odontohypophosphatasia with a primarily dental phenotype, based on a mutation (c.346G>A) identified in a human kindred with autosomal dominant odontohypophosphatasia. Biochemical, skeletal, and dental analyses were performed on the resulting Alpl(+/A116T) mice to validate this model. Alpl(+/A116T) mice featured 50% reduction in plasma ALP activity compared with wild-type controls. No differences in litter size, survival, or body weight were observed in Alpl(+/A116T) versus wild-type mice. The postcranial skeleton of Alpl(+/A116T) mice was normal by radiography, with no differences in femur length, cortical/trabecular structure or mineral density, or mechanical properties. Parietal bone trabecular compartment was mildly altered. Alpl(+/A116T) mice featured alterations in the alveolar bone, including radiolucencies and resorptive lesions, osteoid accumulation on the alveolar bone crest, and significant differences in several bone properties measured by micro-computed tomography. Nonsignificant changes in acellular cementum did not appear to affect periodontal attachment or function, although circulating ALP activity was correlated significantly with incisor cementum thickness. The Alpl(+/A116T) mouse is the first model of odontohypophosphatasia, providing insights on dentoalveolar development and function under reduced ALP, bringing attention to direct effects of HPP on alveolar bone, and offering a new model for testing potential dental-targeted therapies in future studies. © International & American Associations for Dental Research 2015.
    Journal of Dental Research 02/2015; 94(5). DOI:10.1177/0022034515573273 · 4.14 Impact Factor
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    ABSTRACT: We read with interest the letter from Dr. Rossini and colleagues, but found no evidence that our patient's unique syndrome((1)) is secondary to systemic mastocytosis (SM). This boy did not have symptoms of SM, skin examination was unremarkable, leukocyte count and differential were normal, and toluidine staining of his iliac crest specimen did not contain spindle shaped mast cell granulomas characteristic of bone involvement in SM.((2,3)) Excessive numbers of isolated eosinophils or mast cells were not present. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2015; 30(5). DOI:10.1002/jbmr.2455 · 6.83 Impact Factor
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    ABSTRACT: Heritable forms of hypophosphatemic rickets (HR) include X-linked dominant (XLH), autosomal recessive, and autosomal dominant HR (from deactivating mutations in PHEX, or DMP1 or ENPP1, or activating mutations in FGF23, respectively). Over 30 years, we have cared for 284 children with HR. For those 72 deemed sporadic XLH, we preliminarily reported mutation analysis for 30 subjects. Eleven had PHEX mutations. However, the remaining 19 lacked readily identifiable defects in PHEX, DMP1, or FGF23. In 2008, a novel single-base change near the polyadenylation (pA) signal in the 3'-UTR of PHEX was identified in XLH by other investigators. This c.*231A > G mutation is 3-bp upstream of the putative pA signal (AATAAA) in PHEX. Accordingly, we investigated whether this 3'-UTR defect accounted for HR in any of these 19 sporadic XLH patients. PCR amplification and sequencing of their 3'-UTR region showed the c.*231A > G mutation in 4 unrelated boys. Then, among an additional 22 of our 72 “sporadic” XLH patients, one boy and one girl were found to have the 3'-UTR defect, totaling 6 patients. Among these 52 sporadic XLH patients with PHEX analysis, 36 were girls and 16 were boys; i.e., an ∼ 2:1 gender ratio consistent with XLH. However, finding the 5 boys and only one girl with this 3'-UTR mutation presented an unexplained gender bias (p = 0.02). Haplotyping for the 5 boys, all reportedly unrelated, showed a common core haplotype suggesting a founder. Five of their 6 mothers had been studied clinically and biochemically (3 radiologically). Remarkably, the seemingly unaffected mothers of 4 of these boys carried the 3'-UTR mutation. These healthy women had normal height, straight limbs, lacked the radiographic presentation of XLH, and showed normal or slight decreases in fasting serum Pi levels and/or TmP/GFR. Hence, PHEX c.*231A > G can masquerade as sporadic or X-linked recessive HR. © 2014 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2015; 30(1). DOI:10.1002/jbmr.2307 · 6.83 Impact Factor
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    ABSTRACT: Among the high bone mass disorders, the osteopetroses reflect osteoclast failure that prevents skeletal resorption and turnover leading to reduced bone growth and modeling and characteristic histopathological and radiographic findings. We report an 11-year-old boy with a new syndrome that radiographically mimics osteopetrosis but features rapid skeletal turnover. He presented at age 21 months with a parasellar, osteoclast-rich giant cell granuloma. Radiographs showed a dense skull, generalized osteosclerosis, and cortical thickening, medullary cavity narrowing, and diminished modeling of tubular bones. His serum alkaline phosphatase was > 5,000 IU/L (normal < 850). After partial resection, the granuloma re-grew but then regressed and stabilized during three years of uncomplicated pamidronate treatment. His hyperphosphatasemia transiently diminished but all bone turnover markers, especially those of apposition, remained elevated. Two years after pamidronate therapy stopped, BMD z-scores reached + 9.1 and + 5.8 in the lumbar spine and hip, respectively, and iliac crest histopathology confirmed rapid bone remodeling. Serum multiplex biomarker profiling was striking for low sclerostin. Mutation analysis was negative for activation of LRP4, LRP5, or TGFβ1 and for defective SOST, OPG, RANKL, RANK, SQSTM1, or sFRP1. Microarray showed no notable copy number variation. Studies of his non-consanguineous parents were unremarkable. The etiology and pathogenesis of this unique syndrome are unknown. © 2014 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 12/2014; 29(12). DOI:10.1002/jbmr.2289 · 6.83 Impact Factor
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    ABSTRACT: Lenz-Majewski hyperostotic dwarfism (LMHD) is an ultra-rare Mendelian craniotubular dysostosis that causes skeletal dysmorphism and widely distributed osteosclerosis. Biochemical and histopathological characterization of the bone disease is incomplete and non-existent, respectively.In 2014, a publication concerning five unrelated patients with LMHD disclosed that all carried one of three heterozygous missense mutations in PTDSS1 encoding phosphatidylserine synthase 1 (PSS1). PSS1 promotes the biosynthesis of phosphatidylserine (PTDS), which is a functional constituent of lipid bilayers. In vitro, these PTDSS1 mutations were gain-of-function and increased PTDS production. Notably, PTDS binds calcium within matrix vesicles to engender hydroxyapatite crystal formation, and may enhance mesenchymal stem cell differentiation leading to osteogenesis.We report an infant girl with LMHD and a novel heterozygous missense mutation (c.829T > C, p.Trp277Arg) within PTDSS1. Bone turnover markers suggested that her osteosclerosis resulted from reflected accelerated formation with an unremarkable rate of resorption. Urinary amino acid quantitation revealed a greater than six-fold elevation of phosphoserine. Our findings affirm that PTDSS1 defects cause LMHD, and support enhanced biosynthesis of PTDS in the pathogenesis of LMHD. © 2014 American Society for Bone and Mineral Research
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 11/2014; 30(4). DOI:10.1002/jbmr.2398 · 6.83 Impact Factor
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    ABSTRACT: Multicentric carpotarsal osteolysis syndrome (MCTO), an autosomal dominant disorder that often presents sporadically, features carpal–tarsal lysis frequently followed by nephropathy and renal failure. In 2012, mutations in the single-exon gene MAFB were reported in 13 probands with MCTO. MAFB is a negative regulator of RANKL-mediated osteoclastogenesis. We studied nine MCTO patients (seven sporadic patients and one affected mother and son) for MAFB mutation. We PCR-amplified and selectively sequenced the MAFB region that contains the transactivation domain in this 323 amino acid protein, where mutations were previously reported for MCTO. We found five different heterozygous missense defects among eight probands: c.176C > T, p.Pro59Leu; c.185C > T, p.Thr62Ile; c.206C > T, p.Ser69Leu (four had this defect); c.209C > T, p.Ser70Leu; and c.211C > T, p.Pro71Ser. All 5 mutations are within a 13 amino acid stretch of the transactivation domain. Four were identical to the previously reported mutations. Our unique mutation (c.185C > T, p.Thr62Ile) involved the same domain. DNA available from seven parents of the seven sporadic patients did not show their child's MAFB mutation. The affected mother and son had an identical defect. Hence, the mutations for 7/8 probands were suspected to have arisen spontaneously as there was no history of features of MCTO in either parent. Penetrance of MCTO seemed complete. Lack of nonsense or other truncating mutations suggested a dominant-negative pathogenesis. Our findings indicate that only a few transactivation domain-specific mutations within MAFB cause MCTO. © 2014 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 09/2014; 164(9). DOI:10.1002/ajmg.a.36641 · 2.16 Impact Factor
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    ABSTRACT: 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 3years. One femur was congenitally short and curved. Then, both bowed. Deafness at age 2years 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.
    Bone 07/2014; 68. DOI:10.1016/j.bone.2014.07.019 · 3.97 Impact Factor
  • Fiona J Cook · Steven Mumm · Michael P Whyte · Deborah Wenkert ·
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    ABSTRACT: Pregnancy-associated osteoporosis (PAO) is a rare, idiopathic disorder that usually presents with vertebral compression fractures (VCFs) within 6 mo of a first pregnancy and delivery. Spontaneous improvement is typical. There is no known genetic basis for PAO. A 26 yr old primagravida with a neonatal history of unilateral blindness due to hyperplastic primary vitreous sustained postpartum VCFs consistent with PAO. Her low bone mineral density (BMD) seemed to respond to vitamin D and calcium therapy, with no fractures after her next successful pregnancy. Investigation of subsequent fetal losses revealed homozygosity for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism associated both with fetal loss and with osteoporosis (OP). Because her neonatal unilateral blindness and OP were suggestive of loss-of-function mutation(s) in the gene that encodes LDL receptor-related protein 5 (LRP5), LRP5 exon and splice site sequencing was also performed. This revealed a unique heterozygous 12-bp deletion in exon 21 (c.4454_4465del, p.1485_1488del SSSS) in the patient, her mother and sons, but not her father or brother. Her mother had a normal BMD, no history of fractures, PAO, ophthalmopathy, or fetal loss. Her two sons had no ophthalmopathy and no skeletal issues. Her osteoporotic father (with a family history of blindness) and brother had low BMDs first documented at ages ∼ 40 and 32 yrs, respectively. Serum biochemical and bone turnover studies were unremarkable in all subjects. We postulate that our patient's heterozygous LRP5 mutation together with her homozygous MTHFR polymorphism likely predisposed her to low peak BMD. However, OP did not co-segregate in her family with the LRP5 mutation, the homozygous MTHFR polymorphism, or even the combination of the two, implicating additional genetic or non-genetic factors in her PAO. Nevertheless, exploration for potential genetic contributions to PAO may explain part of the pathogenesis of this enigmatic disorder and identify some at risk women.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2014; 29(4). DOI:10.1002/jbmr.2095 · 6.83 Impact Factor
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    ABSTRACT: Hypophosphatasia (HPP) is the inborn-error-of-metabolism that features low serum alkaline phosphatase (ALP) activity caused by loss-of-function mutation(s) within the gene for the tissue nonspecific isoenzyme of ALP (TNSALP). In HPP, extracellular accumulation of inorganic pyrophosphate (PPi), a TNSALP substrate and inhibitor of mineralization, leads frequently to premature tooth loss and often to rickets or osteomalacia. In affected adults, the excess PPi sometimes also causes calcium pyrophosphate dihydrate (CPPD) deposition, PPi arthropathy, or pseudogout, or seemingly paradoxical deposition of hydroxyapatite crystals in ligaments or around joints when the condition is called calcific periarthritis (CP). We report three middle-aged sisters with CP as the only clinical manifestation of HPP. Each presented during early adult life with recurrent episodes of pain principally around the shoulders, elbows, wrists, hips, or Achilles tendon. Otherwise, they were in good health, including no history of unusual dental disease, fractures, or pseudofractures. Calcific deposits were identified in symptomatic areas principally by ultrasonographic assessment, but also confirmed radiographically. All three sisters had low serum levels of total and bone-specific ALP, hyperphosphatemia, and increased serum concentrations of the TNSALP substrate pyridoxal 5'-phosphate together characteristic of HPP. Mutation analysis revealed that each carried a single unique 18-bp duplication within TNSALP (c.188_205dup18, p.Gly63_Thr68dup) as did two of their healthy sons and their mother who was without signs of CPPD deposition or CP but had knee osteoarthritis. We find that CP can be the only complication of HPP in adults. Thus, multiple juxta-articular deposits of hydroxyapatite causing CP may be a useful sign of HPP, especially when the CP is familial. © 2013 American Society for Bone and Mineral Research.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2014; 29(4). DOI:10.1002/jbmr.2110 · 6.83 Impact Factor
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    ABSTRACT: Precise regulation of bone resorption is critical for skeletal homeostasis. We report a 32-year-old man with a panostotic expansile bone disease and a massive hemorrhagic mandibular tumor. Originally from Mexico, he was deaf at birth and became "bow-legged" during childhood. There was no family history of skeletal disease. Puberty occurred normally, but during adolescence, he experienced difficulty straightening his limbs, sustained multiple fractures, and developed a bony tumor on his chin. By age 18 years, all limbs were misshapen. The mandibular mass grew and protruded from the oral cavity, extending to the level of the lower ribs. Other bony defects included a similar maxillary mass and serpentine limbs. Upon referral at age 27 years, biochemical studies showed serum alkaline phosphatase of 1760 U/L (Nl: 29-111) and other elevated bone turnover markers. Radiography of the limbs showed medullary expansion and cortical thinning with severe bowing. Although the jaw tumors were initially deemed inoperable, mandibular mass excision and staged partial maxillectomy were eventually performed. Tumor histopathology showed curvilinear trabeculae of woven bone on a background of hypocellular fibrous tissue. Fibrous dysplasia of bone was suspected, but there was no mutation in codon 201 of GNAS in samples from blood or tumor. His clinical findings, elevated serum markers, and disorganized bone histology suggested amplified receptor activator of nuclear factor-κβ (RANK) signaling, even though his presentation differed from conditions with known constitutive activation of RANK signaling (e.g., familial expansile osteolysis). We found a unique 12 base-pair duplication in the signal peptide of TNFRSF11A, the gene that encodes RANK. No exon or splice site mutations were found in the genes encoding RANK-ligand or osteoprotegerin. Alendronate followed by pamidronate therapies substantially decreased his serum alkaline phosphatase activity. This unique patient expands the known phenotypes of the disorders of RANK signaling activation.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 04/2014; 29(4). DOI:10.1002/jbmr.2094 · 6.83 Impact Factor

  • 03/2014; DOI:10.1530/endoabs.34.P14
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    ABSTRACT: The American Society for Bone and Mineral Research (ASBMR) is well served by the fact that many of those responsible for policy development and implementation have diverse interests and are involved in a variety of activities outside of the Society. Accordingly, the ASBMR requires all ASBMR Officers, Councilors, Committee Chairs, Editors-in-Chief, Associate Editors, and certain other appointed representatives to disclose any real or apparent conflicts of interest (including investments or positions in companies involved in the bone and mineral metabolism field), as well as any duality of interests (including affiliations, organizational interests, and/or positions held in entities relevant to the bone and mineral metabolism field and/or the American Society for Bone and Mineral Research). The committees, task forces, and editorial boards of the ASBMR and its publications carry out the work of the Society on behalf of the membership. The distinct functions of the committees, task forces, and editorial boards are intended to address the broad mission of the ASBMR: to promote excellence in research and education, to integrate basic and clinical science in the field of bone and mineral metabolism, and to facilitate the translation of research into clinical practice and the betterment of human health. Chairs and members of committees, task forces, and editorial boards must assure that they act in these roles in a manner free from commercial bias and that they resolve any conflict or duality of interest or disclose them and then recuse themselves from related deliberations and voting. Below is a summary of disclosures from each task force member.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 01/2014; 29(1). DOI:10.1002/jbmr.1998 · 6.83 Impact Factor

Publication Stats

11k Citations
2,032.67 Total Impact Points


  • 1985-2015
    • Shriners Hospitals for Children
      Tampa, Florida, United States
    • University of Missouri - St. Louis
      Сент-Луис, Michigan, United States
  • 1979-2014
    • Barnes Jewish Hospital
      • • Department of Radiology
      • • Department of Nephrology
      San Luis, Missouri, United States
  • 1978-2014
    • Washington University in St. Louis
      • • Department of Medicine
      • • Division of Bone and Mineral Diseases
      San Luis, Missouri, United States
  • 2007
    • Case Western Reserve University
      Cleveland, Ohio, United States
  • 2006
    • University of Saskatchewan
      Saskatoon, Saskatchewan, Canada
  • 2005
    • University of Oviedo
      Oviedo, Asturias, Spain
    • University of Texas Southwestern Medical Center
      • Department of Pediatrics
      Dallas, TX, United States
  • 2004
    • Boston Children's Hospital
      • Division of Genetics
      Boston, MA, United States
  • 1999
    • University of Wisconsin, Madison
      • Department of Medical Genetics
      Madison, MS, United States
  • 1995
    • Medical College of Wisconsin
      Milwaukee, Wisconsin, United States
    • St. Luke's Hospital (MO, USA)
      Сент-Луис, Michigan, United States
    • WWF United Kingdom
      Londinium, England, United Kingdom
  • 1986
    • Dalhousie University
      Halifax, Nova Scotia, Canada