M P Whyte

Shriners Hospitals for Children, Tampa, Florida, United States

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Publications (247)1841 Total impact

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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; · 6.04 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; · 6.04 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; · 4.46 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 07/2014; · 2.30 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 07/2014; · 6.04 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 06/2014; · 6.04 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 10/2013; · 6.04 Impact Factor
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    ABSTRACT: Context:Hypophosphatasia (HPP) features deficient activity of the "tissue-nonspecific" isoenzyme of alkaline phosphatase (TNSALP) due to loss-of-function mutation(s) within the TNSALP gene. Consequently, inorganic pyrophosphate, a TNSALP substrate and inhibitor of mineralization, accumulates extracellularly. This can cause rickets or osteomalacia.Objective:We report a 55-year-old man with HPP and chronic renal failure (CRF) requiring hemodialysis who developed severe hypercalcemia acutely after traumatic fractures and immobilization. He manifested HPP in childhood and in middle age received hemodialysis for CRF attributed to hypertension and anti-inflammatory medication. He took 2 g of calcium carbonate orally each day to bind dietary phosphorus, but never aluminum hydroxide or any form of vitamin D. Pretrauma serum levels of calcium spanned 8.4-10.7 mg/dL (normal [Nl], 8.6-10.3), inorganic phosphate 5.8-6.4 mg/dL (Nl, 2.5-4.5), and PTH 63-75 pg/mL (Nl, 10-55).Results:Rapid succession falls fractured multiple major bones. Six hours later, he became confused. Serum calcium was 14.9 mg/dL, ionized calcium was 7.4 mg/dL (Nl, 4.5-5.1), and PTH was 16 pg/mL. Hemodialysis quickly corrected his hypercalcemia and confusion. Low serum alkaline phosphatase persisted, and follow-up skeletal histopathology showed that his osteomalacia was severe.Conclusion:Hemodialysis does not heal the skeletal disease of HPP. During sudden fracture immobilization in HPP, sufficient calcium can emerge from bone, perhaps from a rapidly exchangeable calcium pool, to cause acute severe hypercalcemia if the kidneys cannot compensate for the mineral efflux. Hence, we worry that acute hypercalcemia might accompany sudden immobilization in CRF patients without HPP if they have adynamic bone disease.
    The Journal of Clinical Endocrinology and Metabolism 09/2013; · 6.31 Impact Factor
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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 09/2013; · 6.04 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 09/2013; · 6.04 Impact Factor
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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 05/2013; · 6.04 Impact Factor
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    ABSTRACT: Hypophosphatasia (HPP) is the metabolic bone disease caused by loss-of-function mutation within the gene that encodes the "tissue nonspecific" isoenzyme of alkaline phosphatase (TNSALP). Perinatal HPP is usually fatal due to respiratory insufficiency, and infantile HPP often has a similar outcome although no formal study into the natural history of these severe forms of HPP has been undertaken. We reviewed our 80-year (1927-2007) cohort of 15 Canadian patients with perinatal HPP. All had Mennonite heritage. Family linkage studies indicated that nine were homozygous for a TNSALP disease allele, likely Gly334Asp. Three patients had parents who were carriers for the Gly334Asp allele by mutation analysis. One patient was confirmed by mutation analysis to be homozygous for the TNSALP Gly334Asp mutation. One patient who had only one Mennonite parent was a genetic compound for the Gly334Asp mutation and the Val382Ile mutation. This patient's sibling was also affected. All 15 patients had profound skeletal hypomineralization, severe rickets, and respiratory insufficiency. All died by 9 months of age, usually soon after birth, from pulmonary failure.
    JIMD reports. 04/2013;
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    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. © 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 01/2013; · 6.04 Impact Factor
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    ABSTRACT: Adaptor protein-2 (AP2), a central component of clathrin-coated vesicles (CCVs), is pivotal in clathrin-mediated endocytosis, which internalizes plasma membrane constituents such as G protein-coupled receptors (GPCRs). AP2, a heterotetramer of α, β, μ and σ subunits, links clathrin to vesicle membranes and binds to tyrosine- and dileucine-based motifs of membrane-associated cargo proteins. Here we show that missense mutations of AP2 σ subunit (AP2S1) affecting Arg15, which forms key contacts with dileucine-based motifs of CCV cargo proteins, result in familial hypocalciuric hypercalcemia type 3 (FHH3), an extracellular calcium homeostasis disorder affecting the parathyroids, kidneys and bone. We found AP2S1 mutations in >20% of cases of FHH without mutations in calcium-sensing GPCR (CASR), which cause FHH1. AP2S1 mutations decreased the sensitivity of CaSR-expressing cells to extracellular calcium and reduced CaSR endocytosis, probably through loss of interaction with a C-terminal CaSR dileucine-based motif, whose disruption also decreased intracellular signaling. Thus, our results identify a new role for AP2 in extracellular calcium homeostasis.
    Nature Genetics 12/2012; · 29.65 Impact Factor
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    ABSTRACT: Generalized arterial calcification (AC) of infancy (GACI) is an autosomal recessive disorder that features hydroxyapatite deposition within arterial elastic fibers. Untreated, approximately 85% of GACI patients die by six months-of-age from cardiac ischemia and congestive heart failure. The first-generation bisphosphonate etidronate (EHDP) inhibits bone resorption and can mimic endogenous inorganic pyrophosphate by blocking mineralization. With EHDP therapy for GACI, AC may resolve without recurrence upon treatment cessation. Skeletal disease is not an early characteristic of GACI, but rickets can appear from acquired hypophosphatemia or prolonged EHDP therapy. We report a 7-year-old boy with GACI referred for profound, acquired, skeletal disease. AC was gone after five months of EHDP therapy during infancy, but GACI-related joint calcifications progressed. He was receiving EHDP, 200 mg/day orally, and had odynodysphagia, diffuse opioid-controlled pain, plagiocephaly, facial dysmorphism, joint calcifications, contractures, and was wheelchair bound. Biochemical parameters of mineral homeostasis were essentially normal. Serum osteocalcin was low and the brain isoform of creatine kinase and TRAP-5b were elevated as in osteopetrosis. Skeletal radiographic findings resembled pediatric hypophosphatasia with pancranial synostosis, long-bone bowing, widened physes, as well as metaphyseal osteosclerosis, cupping and fraying, and "tongues" of radiolucency. Radiographic features of osteopetrosis included osteosclerosis and femoral Erlenmeyer flask deformity. After stopping EHDP, he improved rapidly, including remarkable skeletal healing and decreased joint calcifications. Profound, but rapidly reversible, inhibition of skeletal mineralization with paradoxical calcifications near joints can occur in GACI from protracted EHDP therapy. Although EHDP treatment is life-saving in GACI, surveillance for toxicity is crucial. © 2012 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 09/2012; · 6.04 Impact Factor
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    ABSTRACT: Dysosteosclerosis (DSS) is the form of osteopetrosis distinguished by the presence of skin findings such as red-violet macular atrophy, platyspondyly and metaphyseal osteosclerosis with relative radiolucency of widened diaphyses. At the histopathological level, there is a paucity of osteoclasts when the disease presents. In two patients with DSS, we identified homozygous or compound heterozygous missense mutations in SLC29A3 by whole-exome sequencing. This gene encodes a nucleoside transporter, mutations in which cause histiocytosis-lymphadenopathy plus syndrome, a group of conditions with little or no skeletal involvement. This transporter is essential for lysosomal function in mice. We demonstrate the expression of Slc29a3 in mouse osteoclasts in vivo. In monocytes from patients with DSS, we observed reduced osteoclast differentiation and function (demineralization of calcium surface). Our report highlights the pleomorphic consequences of dysfunction of this nucleoside transporter, and importantly suggests a new mechanism for the control of osteoclast differentiation and function.
    Human Molecular Genetics 08/2012; 21(22):4904-9. · 6.68 Impact Factor
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    ABSTRACT: Idiopathic multicentric osteolysis (IMO) is an uncommon disease presenting during childhood with resorption of the carpus and tarsus with nephropathy. The few case reports and literature reviews do not focus on the upper extremity disease manifestations or surgical treatment options. We review our experience with the upper extremity in IMO. We evaluated 8 affected children, specifically assessing early disease manifestations, misdiagnoses, radiographic progression, and surgical treatments rendered. Wrist pain and swelling are typically the first manifestations of IMO. Characteristic upper extremity findings, once the disease has progressed, include metacarpophalangeal joint hyperextension, wrist ulnar deviation and flexion, and loss of elbow extension. Radiographically, there is osteolysis of the carpus and proximal metacarpals with resorption of the elbow joint in some patients. Surgical treatments, including soft tissue release with pinning or joint arthrodesis, may offer pain relief and improve alignment, but outcomes are inconsistent. Children with IMO are almost always misdiagnosed initially, and the correct diagnosis may be delayed by years. The hand surgeon is ideally suited to provide an accurate diagnosis of IMO, because wrist pain and swelling and thumb interphalangeal joint contracture are common early manifestations. Prognostic IV.
    The Journal of hand surgery 07/2012; 37(8):1677-83. · 1.33 Impact Factor
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    ABSTRACT: Context: Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known. Objective: We report a unique case of hypercalcemia associated with post-essential thrombocythemia myelofibrosis and review the clinical and laboratory features, pathogenesis, and responsiveness to treatment with the bone antiresorptive agent, denosumab. Results: A 62-yr-old woman with essential thrombocythemia presented with progression to myelofibrosis with lytic skull lesions and symptomatic hypercalcemia. Other causes of hypercalcemia were excluded. Her disturbance in calcium homeostasis was not PTH- or vitamin D-mediated, although this has been postulated in cases of hypercalcemia with the related entity of primary myelofibrosis. Her hypercalcemia was refractory to aggressive iv saline administration, furosemide, calcitonin, and pamidronate, but promptly improved after one 120-mg sc dose of the anti-receptor activator of nuclear factor κB (RANK) ligand monoclonal antibody, denosumab, with sustained normocalcemia for approximately 2 months. She died 6 months later from complications due to the leukemic transformation of her hematological disease. Conclusion: The pathogenesis of myelofibrosis-related hypercalcemia could be due to multiple factors, particularly changes in the RANK ligand-RANK-osteoprotegerin system that lead to increased osteoclast activity. Although we did not measure these factors, denosumab holds promise in the treatment of malignancy-associated hypercalcemia and specifically that related to myelofibrosis. Hypercalcemia associated with myelofibrosis is rare, and its pathogenesis and treatment are not known.
    The Journal of Clinical Endocrinology and Metabolism 06/2012; 97(9):3051-5. · 6.31 Impact Factor
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    ABSTRACT: Mucopolysaccharidosis type VII (MPS VII) is characterized by deficient β-glucuronidase (GUSB) activity, which leads to accumulation of chondroitin, heparan and dermatan sulfate glycosaminoglycans (GAGs), and multisystemic disease. MPS VII patients can develop kypho-scoliotic deformity and spinal cord compression due to disease of intervertebral disks, vertebral bodies, and associated tissues. We have previously demonstrated in MPS VII dogs that intervertebral disks degenerate, vertebral bodies have irregular surfaces, and vertebral body epiphyses have reduced calcification, but the pathophysiological mechanisms underlying these changes are unclear. We hypothesized that some of these manifestations could be due to upregulation of destructive proteases, possibly via the binding of GAGs to Toll-like receptor 4 (TLR4), as has been proposed for other tissues in MPS models. In this study, the annulus fibrosus of the intervertebral disk of 6-month-old MPS VII dogs had cathepsin B and K activities that were 117- and 2-fold normal, respectively, which were associated with elevations in mRNA levels for these cathepsins as well as TLR4. The epiphyses of MPS VII dogs had a marked elevation in mRNA for the cartilage-associated gene collagen II, consistent with a developmental delay in the conversion of the cartilage to bone in this region. The spine obtained at autopsy from a young man with MPS VII exhibited similar increased cartilage in the vertebral bodies adjacent to the end plates, disorganization of the intervertebral disks, and irregular vertebral end plate morphology. These data suggest that the pathogenesis of destructive changes in the spine in MPS VII may involve upregulation of cathepsins. Inhibition of destructive proteases, such as cathepsins, might reduce spine disease in patients with MPS VII or related disorders.
    Molecular Genetics and Metabolism 03/2012; 107(1-2):153-60. · 2.83 Impact Factor
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    ABSTRACT: Hypophosphatasia (HPP) is the inborn error of metabolism characterized by deficiency of alkaline phosphatase activity, leading to rickets or osteomalacia and to dental defects. HPP occurs from loss-of-function mutations within the gene that encodes the tissue-nonspecific isozyme of alkaline phosphatase (TNAP). TNAP knockout (Alpl(-/-), aka Akp2(-/-)) mice closely phenocopy infantile HPP, including the rickets, vitamin B6-responsive seizures, improper dentin mineralization, and lack of acellular cementum. Here, we report that lack of TNAP in Alpl(-/-) mice also causes severe enamel defects, which are preventable by enzyme replacement with mineral-targeted TNAP (ENB-0040). Immunohistochemistry was used to map the spatiotemporal expression of TNAP in the tissues of the developing enamel organ of healthy mouse molars and incisors. We found strong, stage-specific expression of TNAP in ameloblasts. In the Alpl(-/-) mice, histological, µCT, and scanning electron microscopy analysis showed reduced mineralization and disrupted organization of the rods and inter-rod structures in enamel of both the molars and incisors. All of these abnormalities were prevented in mice receiving from birth daily subcutaneous injections of mineral-targeting, human TNAP at 8.2 mg/kg/day for up to 44 days. These data reveal an important role for TNAP in enamel mineralization and demonstrate the efficacy of mineral-targeted TNAP to prevent enamel defects in HPP.
    Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 03/2012; 27(8):1722-34. · 6.04 Impact Factor

Publication Stats

7k Citations
1,841.00 Total Impact Points


  • 1986–2014
    • Shriners Hospitals for Children
      Tampa, Florida, United States
  • 2013
    • University of Barcelona
      Barcino, Catalonia, Spain
    • Shiraz University of Medical Sciences
      Chimaz, Fārs, Iran
    • University of South Carolina School of Medicine - Greenville
      Greenville, South Carolina, United States
  • 2012
    • University of British Columbia - Vancouver
      Vancouver, British Columbia, Canada
  • 2005–2012
    • University of Oxford
      • Nuffield Department of Clinical Medicine
      Oxford, ENG, United Kingdom
    • University of Texas Southwestern Medical Center
      • Department of Pediatrics
      Dallas, TX, United States
  • 1981–2012
    • Washington University in St. Louis
      • • Department of Orthopaedic Surgery
      • • Division of Bone and Mineral Diseases
      • • Department of Medicine
      Saint Louis, MO, United States
  • 2011
    • Emory University
      • Department of Internal Medicine
      Atlanta, GA, United States
  • 2010
    • New Mexico Clinical Research and Osteoporosis Center
      Albuquerque, New Mexico, United States
  • 2007–2010
    • Columbia University
      • • College of Physicians and Surgeons
      • • Department of Medicine
      New York City, NY, United States
  • 2008
    • Sanford-Burnham Medical Research Institute
      La Jolla, California, United States
    • University of Utah
      • Department of Pediatrics
      Salt Lake City, UT, United States
  • 1987–2008
    • Barnes Jewish Hospital
      • Department of Nephrology
      San Luis, Missouri, United States
  • 2006
    • University of Saskatchewan
      Saskatoon, Saskatchewan, Canada
    • Harvard Medical School
      Boston, Massachusetts, United States
  • 1988–2006
    • University of Washington Seattle
      • • Division of General Internal Medicine
      • • Department of Radiology
      • • Department of Medicine
      Seattle, WA, United States
    • Case Western Reserve University School of Medicine
      Cleveland, Ohio, United States
  • 1988–2005
    • Hospital of the University of Pennsylvania
      • • Division of Endocrinology Diabetes and Metabolism
      • • Department of Genetics
      Philadelphia, Pennsylvania, United States
  • 2004
    • Boston Children's Hospital
      • Division of Genetics
      Boston, MA, United States
  • 2001
    • Oxford University Hospitals NHS Trust
      Oxford, England, United Kingdom
  • 1994–2000
    • University of Missouri - St. Louis
      Saint Louis, Michigan, United States
  • 1999
    • National Research Council
      • Institute of Biomedical Technologies ITB
      Roma, Latium, Italy
    • Indiana University-Purdue University Indianapolis
      • Department of Medical and Molecular Genetics
      Indianapolis, IN, United States
    • University of Wisconsin, Madison
      • Department of Medical Genetics
      Madison, MS, United States
  • 1997–1999
    • MRC Clinical Sciences Centre
      London Borough of Harrow, England, United Kingdom
    • Childrens Hospital of Pittsburgh
      • Department of Pediatrics
      Pittsburgh, Pennsylvania, United States
    • Ulsan University Hospital
      Urusan, Ulsan, South Korea
  • 1998
    • Kansas City VA Medical Center
      Kansas City, Missouri, United States
    • Aurora St. Luke's Medical Center
      Milwaukee, Wisconsin, United States
  • 1992–1995
    • University of Pennsylvania
      • School of Veterinary Medicine
      Philadelphia, PA, United States