Michael P. Whyte

Washington University in St. Louis, San Luis, Missouri, United States

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Publications (294)2103.47 Total impact

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    ABSTRACT: We report auricular ossification (AO) affecting the elastic cartilage of the ear as a newly recognized feature of osteoprotegerin (OPG)-deficiency juvenile Paget disease (JPD). AO and auricular calcification refer interchangeably to rigid pinnae, sparing the ear lobe, from various etiologies. JPD is a rare Mendelian disorder characterized by elevated serum alkaline phosphatase activity accompanied by skeletal pain and deformity from rapid bone turnover. Autosomal recessive transmission of loss-of-function mutations within TNFRSF11B encoding OPG accounts for most JPD (JPD1). JPD2 results from heterozygous constitutive activation of TNFRSF11A encoding RANK. Other causes of JPD remain unknown. In 2007, we reported a 60-year-old man with JPD1 who described hardening of his external ears at age 45 years, after 4 years of treatment with bisphosphonates (BPs). Subsequently, we noted rigid pinnae in a 17-year-old boy and 14-year-old girl, yet pliable pinnae in a 12-year-old boy, each with JPD1 and several years of BP treatment. Cranial imaging indicated cortical bone within the pinnae of both teenagers. Radiologic studies of our three JPD patients without mutations in TNFRSF11B showed normal auricles. Review of the JPD literature revealed possible AO in several reports. Two of our JPD1 patients had experienced difficult tracheal intubation, raising concern for mineralization of laryngeal elastic cartilage. Thus, AO is a newly recognized feature of JPD1, possibly exacerbated by BP treatment. Elastic cartilage at other sites in JPD1 might also ossify, and warrants investigation. © 2016 Wiley Periodicals, Inc.
    No preview · Article · Jan 2016 · American Journal of Medical Genetics Part A
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    ABSTRACT: Congenital insensitivity to pain (CIP) comprises the rare heritable disorders without peripheral neuropathy that feature inability to feel pain. Fracturing and joint destruction are common complications, but lack detailed studies of mineral and skeletal homeostasis and bone histology. In 2013, discovery of a heterozygous gain-of-function mutation in SCN11A encoding voltage-gated sodium channel 1.9 (Nav1.9) established a distinctive CIP in three unrelated patients who suffered multiple painless fractures, self-inflicted mutilation, chronic diarrhea, and hyperhidrosis.
    No preview · Article · Dec 2015 · Bone
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    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.
    Preview · Article · Nov 2015 · Calcified Tissue International
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    ABSTRACT: Context: Hypophosphatasia (HPP) is an inborn error of metabolism that, in its most severe perinatal and infantile forms, results in 50-100% mortality, typically from respiratory complications. Objective: To better understand the effect of treatment with asfotase alfa, a first-in-class enzyme replacement therapy, on mortality in neonates and infants with severe HPP. Design/setting: Data from patients with the perinatal and infantile forms of HPP in two ongoing, multicenter, multinational, open-label, phase 2 interventional studies of asfotase alfa treatment were compared with data from similar patients from a retrospective natural history study. Patients: Thirty-seven treated patients (median treatment duration 2.7 years) and 48 historical controls of similar chronological age and HPP characteristics. Interventions: Treated patients received asfotase alfa as subcutaneous injections either 1 mg/kg 6 times per week or 2 mg/kg 3 times per week. Main outcome measures: Survival, skeletal health quantified radiographically on treatment, and ventilatory status. Results: Asfotase alfa was associated with improved survival in treated patients versus historical controls: 95% versus 42% at age 1 year, and 84% versus 27% at age 5 years, respectively (P<0.0001, Kaplan-Meier log-rank test). Whereas 5% (1/20) of the historical controls who required ventilatory assistance survived, 76% (16/21) of the ventilated and treated patients survived, among whom 75% (12/16) weaned from ventilatory support. This better respiratory outcome accompanied radiographic improvements in skeletal mineralization and health. Conclusions: Asfotase alfa mineralizes the HPP skeleton, including the ribs, and improves respiratory function and survival in life-threatening perinatal and infantile HPP.
    No preview · Article · Nov 2015 · The Journal of Clinical Endocrinology and Metabolism

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  • No preview · Article · Aug 2015
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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.
    Full-text · Article · Jul 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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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.
    Preview · Article · Jun 2015 · Human Molecular Genetics

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  • No preview · Article · Jun 2015
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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.
    Full-text · Article · May 2015 · Nature Genetics
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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.
    No preview · Article · Feb 2015 · Bone
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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.
    Full-text · Article · Feb 2015 · Journal of Dental Research
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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.
    No preview · Article · Jan 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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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
    No preview · Article · Jan 2015 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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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.
    No preview · Article · Dec 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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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
    No preview · Article · Nov 2014 · Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research
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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.
    No preview · Article · Sep 2014 · American Journal of Medical Genetics Part A
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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.
    No preview · Article · Jul 2014 · Bone

Publication Stats

12k Citations
2,103.47 Total Impact Points

Institutions

  • 1978-2015
    • Washington University in St. Louis
      • • Division of Bone and Mineral Diseases
      • • Department of Medicine
      San Luis, Missouri, United States
  • 1973-2015
    • Shriners Hospitals for Children
      Tampa, Florida, United States
  • 1979-2014
    • Barnes Jewish Hospital
      • • Department of Radiology
      • • Department of Nephrology
      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
    • WWF United Kingdom
      Londinium, England, United Kingdom
    • Medical College of Wisconsin
      Milwaukee, Wisconsin, United States
  • 1981-1995
    • St. Luke's Hospital (MO, USA)
      Сент-Луис, Michigan, United States
  • 1988
    • Middlesex Hospital
      मिडलटाउन, Connecticut, United States
  • 1986
    • Dalhousie University
      Halifax, Nova Scotia, Canada
  • 1985
    • University of Missouri - St. Louis
      Сент-Луис, Michigan, United States
  • 1982
    • University of Wisconsin - Milwaukee
      Milwaukee, Wisconsin, United States