UCSF Osher Center for Integrative Medicine

Mini Medical School for the Public FALL 2013 – Wednesday Course Series MEDICAL DETECTIVES: INSIDE THE MIND OF GREAT PHYSICIANS Date: Wednesday, October 16, 2013, 7:00 pm – 8:45 pm Topic: VACCINES: MYSTERIES: FOP –WHEN BODIES TURN TO BONE Speaker: Joseph A. Kitterman, MD, Professor Emeritus of Pediatrics and the Cardiovascular Research Institute Joseph A. Kitterman, M.D. is Professor Emeritus of Pediatrics and the Cardiovascular Research Institute at UCSF and a staff physician at UCSF Benioff Children’s Hospital. He received a B.A. in Zoology from UC Berkeley and received his medical degree from McGill University in Montreal, Quebec, Canada. After interning at the Montreal General Hospital, he completed a residency in Pediatrics and a fellowship in cardiopulmonary physiology at UCSF. He is board certified in Pediatrics and Neonatal-Perinatal Medicine. While a UCSF faculty member (1970 to 2007), he was an attending physician in the William H. Tooley Intensive Care Nursery, directed the Neonatology Fellowship Program for 19 years, and was Medical Director of the Neonatal Clinical Physiology Laboratory for 20 years. He has extensive experience in clinical research and in laboratory research (developmental lung biology). Since 2000, he has been active in clinical research in FOP and in the care of patients with the disease.

Bibliography: *International FOP Association: www.ifopa.org

Kaplan FS, Le Merrer M, Glaser DL, et al: Fibrodysplasia ossificans progressiva. Best Practice & Research Clinical Rheumatology 2008;22: 191-205.

Kaplan, FS, Zasloff MA, Kitterman JA, et al: Early mortality from cardiorespiratory failure in patients with fibrodysplasia ossificans progressiva. Journal of Bone and Joint Surgery 2010;92: 686-691.

Kitterman JA, Kantanie S, Rocke DM, Kaplan FS: Iatrogenic harm caused by diagnostic errors in fibrodysplasia ossificans progressiva. Pediatrics 2005;116: e654-e661.

UCSF Osher Center for Integrative Medicine

Mini Medical School for the Public Kitterman JA, Strober JB, Kan L, et al: Neurological symptoms in individuals with fibrodysplasia ossificans progressiva. Journal of Neurology, 2012;259: 2636-2643.

*Maeder T: A few hundred people turned to bone. The Atlantic February, 1998: http://www.theatlantic.com/magazine/archive/1998/02/a-few-hundred-people-turned-tobone/304887/

Nussbaum BL, Grunwald Z, Kaplan FS: Oral and dental health care and anesthesia for persons with fibrodysplasia ossificans progressiva. Clinical Reviews in Bone and Mineral Metabolism 2005;3: 239-42.

Rosenstirn J: A contribution to the study of myositis ossificans progressiva. Annals of Surgery 1918;68:485-520 and 591-637.

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Genetic Mysteries:  Fibrodysplasia Ossificans Progressiva (FOP),  When Bodies Turn to Bone  UCSF Mini‐Medical School October 16, 2013 Joseph A. Kitterman, M.D. Professor Emeritus of Pediatrics and  the Cardiovascular Research Institute

What  is  FOP? • Rare, devastating genetic condition in which  skeletal muscles, tendons and ligaments  progressively and permanently turn to bone • Almost all cases are new mutations • Characterized by: – Distinctive malformations of the great toes: short  with lateral deviation (hallux valgus) – “Flare‐ups,” tumor‐like lesions that progress to  ossification (bone formation)

• Most cases are initially given incorrect diagnoses • No effective treatment

Major Clinical Features of FOP Why is an old, retired  neonatologist and lung biologist  speaking about a very rare bone  disease that is almost never  diagnosed before age 3 years? Short great toes with  valgus deviation

FOP Flare‐up

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‐Born at term with unusual short great toes ‐Pediatrician asked: “Whose toes does he have, mom’s or dad’s? ‐Played Little League baseball ‐Tried out for high school football team ‐Avid wake‐boarder ‐Age 17, fell while wakeboarding and felt pain in neck ‐Mass arose on back ‐Biopsies: (1) probable lymphoma; (2) aggressive fibromatosis ‐Chemotherapy ‐Follow‐up CT scan: Dx’ed by radiologist as FOP 

FOP is not a new disease • 1692: Patin (France) described a woman who  gradually became “hard like wood.” • 1738‐40: Three cases described in letters to the  Royal Society (England) • 1918: Rosenstirn reported a case and  reviewed 120 cases from   the literature (Annals of  Surgery 68:485). Julius Rosenstirn, M.D. Mt. Zion Hospital, San Francisco

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Number  of  FOP  Papers

40

FOP Articles by Year

35 30 25 20 15 10 5

Frederick S. Kaplan, M.D.

0 1981

1986

1991

1996

2001

2006

2011

Year

Frederick Kaplan, M.D. • Orthopaedic surgeon • 1989: First saw child with FOP • 1989 to 1991: Research fellow in human genetics and  molecular biology with Michael Zasloff, M.D., Ph.D. • Since then has devoted his career to FOP research  and care of FOP patients • Newsweek, 2006: “One of the 15 people who make  America great.”

Isaac & Rose Nassau Professor of Orthopaedic Molecular Medicine Director, Center for Research in FOP & Related Disorders University of Pennsylvania School of Medicine

Fibrodysplasia Ossificans Progressiva • Rare genetic disease characterized by:            ‐malformations of the great toes ‐episodic progressive heterotopic ossification • Incidence: one in 2 million worldwide (no differences by gender, race, ethnicity,  or geographical location)

• Autosomal dominant, 100% penetrance with  variable expressivity • Progressive & permanent loss of mobility • Cause is an activating mutation of the Type 1 BMP  receptor, ACVR1 • No effective treatment

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Malformations of the Great Toes in FOP

Early  FOP  Lesions (Flare‐ups) • Most commonly occur first on back, head, neck or shoulders • Lesions are warm, red and tender • Appear very rapidly, often overnight

Short great toes Hallux valgus deformity Absent or hypoplastic 1st phalanx Malformations are present at birth

FOP is a Metamorphosis

FOP Bone Perivascular Lymphocytic Infiltration

Fibro‐ Proliferation/ Angiogenesis

Intramuscular Lymphocytic Infiltration

Chondrocyte Condensation

Muscle Degradation

Endochondral Ossification

Normal • Histologically Abnormal • Biochemically • Wrong time • Metabolically •Wrong places • Physically • Radiographically

(Kaplan FS, Tabas JA, et al., J Bone Joint Surg Am, 1993)

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Progression  of  FOP • FOP affects:  ‐Striated muscle ‐Ligaments

‐Tendons ‐Fasciae

• FOP spares: ‐Diaphragm ‐Extra‐ocular muscles ‐Tongue ‐Cardiac & smooth muscle ‐Small muscles of hand (usually) • Progression of FOP: ‐Cranial to caudal ‐Axial to peripheral (Cohen, et al., J Bone Joint Surg Am, 1993)

Progression of FOP

Clinical Aspects of FOP • Toe malformations are present at birth • Onset of flare‐ups usually in first decade of life • Usually misdiagnosed initially • Flare‐ups may be: ‐spontaneous ‐triggered by trauma: Falls IM injections Biopsies Surgery ‐a result of a viral infection

• Surgical removal of FOP bone causes rapid,  explosive regrowth of bone

Progressive Heterotopic Ossification (In an 11 year old boy)

Repeated flare‐ups Increasing heterotopic ossification Progressive & permanent loss of mobility

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Harry Eastlack

Chin‐on Chest Deformity in FOP

1935 to 1972

4 years

7 years

9 years

Harry’s skeleton  can be seen in the  Mütter Museum in Philadelphia 8 year old girl: Deformity developed over 3 years 11 years

18 years

1973

Other Features of FOP • Mild hearing loss in ~50% of patients • Neurological complications – Headaches* – Neuropathic pain* – Sensory abnormalities* – Myoclonus* – Demyelinating lesions of CNS

• Characteristic facial pattern – Receding jaw – Under‐developed mid‐facial area * Only in post‐pubertal females

FOP patients at UCSF in past 13 years • 2000, 17 y.o. male with masses on neck, back and chest  presented at Pediatric Tumor Board • 2003, 3 y.o. male with neck masses • 2005, 17 y.o. male seen in Orthopaedics Clinic • 2006, 23 y.o. female admitted to Medicine with severe  flare‐up of arm • 2006, 18 month male admitted to Pediatrics with a stiff  neck and masses on neck, back and forehead • 2007, 29 y.o. Swedish female admitted to Orthopaedics with multiple fractures from MVA • 2007‐2013, 19 y.o. female admitted 25 times to Pediatrics  with neurological symptoms

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FOP Meeting for Teens and Young Adults San Diego, 2009

Diagnostic Errors in FOP • Survey: 138 individuals with FOP from 25 countries • 87% initially received incorrect diagnoses • Physicians seen before correct DX: 

‐ x=6, range: 1 to 51

• Incorrect diagnoses included – Cancer (32): lymphoma – Fibromatosis (19): aggressive fibromatosis and desmoid tumors – Bunions or hallux valgus (9) – Overuse injuries (7) – 43 other diagnoses

• 67% underwent biopsies • 49% reported permanent loss of function due to  inappropriate medical interventions (Kitterman, et al. Pediatrics, 2005)

Catastrophic Misdiagnosis  In FOP

Paucity  of  FOP  Information  in Medical Textbooks Type of book n FOP • Oncology 18 3 • Internal Med.           19 3 • Metabol. Bone Dis. 13 8 • Genetics 16 9 • Orthopaedics 35     12 • Podiatry 18 4 • Pediatrics 30 5 • Ped. Ortho. 13           4 • Ped. Oncology          14 1 • Neonatology 8 0

• Total 184      29% • Total Pediatrics  65      15%

Great Toes 2 3 8 7 7 3     3 3 1 0

20% 11%

Trauma 2 2 5  4 1 0 0 0 1 0

8% 2%

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Medical Management of FOP • • • • •

Make an accurate diagnosis Avoid trauma (IM injections, biopsies, surgery, falls, fatigue) Muscle relaxants NSAIDs for pain relief  (Vioxx was banned) For flare‐ups involving new joints or airway, jaw,  or throat: – High dose adrenal corticoids for 3 to 4 days – Repeat if flare‐up persists

• Amino‐bisphosphonates may help in flare‐ups • Currently, no proven effective treatment

Outcome in FOP • Recurrent flare‐ups leading to ossification • Progressive & permanent loss of mobility • Most are wheelchair bound by the 3rd decade (Cohen,  et al., J Bone Joint Surg Am, 1993)

• May need assisted care for basic personal functions • Malnutrition, especially after inappropriate dental work • Progressive worsening of cardio‐pulmonary function due to  restrictive lung disease     (Kussmaul, et al., Clin Othop Relat Res, 1998) • Early death (median age 40 years, range 3 ‐ 77 years) • Causes of death: ‐Cardio‐respiratory failure   (54%) ‐Pneumonia  (15%) ‐Falls  (11%) (Kaplan, et al., J Bone Joint Surg Am, 2010)

Special Considerations in FOP • Dental procedures: Avoid permanent locking of jaw – No mandibular blocks – Do not stretch mouth open

• General anesthesia – No oro‐tracheal intubation – Use naso‐tracheal intubation – Careful positioning to avoid pressure trauma

Genetic Cause of FOP • Activating mutation in gene encoding for the type 1  bone morphogenetic protein (BMP) receptor, ACVR1  (Alk2), on chromosome 2q • Identical single nucleotide change in 45 individuals  with FOP • Mutation was absent in 159 individuals without FOP (Shore, et al., Nature Genetics, 2006)

• Mutation results in: ‐Over‐expression of BMP4 mRNA ‐Failure to upregulate BMP antagonists ‐Ligand independent BMP signaling ‐↑ responsiveness in presence of ligand ‐↓ BMP receptor internalization/degradation (Shore & Kaplan, Bone, 2008)

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Recent Research Advances in FOP 2004  FOPPY mouse over‐expresses BMP4 2006  Discovery of FOP gene 2007  Flare‐up cells are endothelial in origin 2010  Conversion of endothelial cells to stem cells 2011  RAR‐ϒ agonists inhibit H.O. 2011  Substance P mediates BMP dependent H.O. 2011  “Strategies for Treatment of FOP,” Scientific Workshop at U. Penn. • 2012  Transgenic mouse model of FOP • ?       Clinical trial of treatment for FOP • • • • • • •

Transgenic Mouse Model of FOP

Transgenic Mouse Model of FOP Toe Malformations of Hind Limb First Digit

FOP Mouse

Control

Comparison of Human and Mouse FOP Abnormality Human Malformed great toes + Heterotopic ossification + Fusion of vertebrae + Short, broad femoral necks + Malform’n of costo‐vert. joints + Osteochondromas + Inflammationn/lymphocyte   + infiltrationn

Mouse +  + +  +  +  +  + 

(Chakkalakal, et al, 2012) 

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FOP Research and Care at UCSF

www.ifopa.org

Edward Hsiao, M.D., Ph.D. Division of Endocrinology Dept. of Medicine

Stem cell research in FOP Metabolic Bone Clinic   (415) 353‐2350 In‐patient care of FOP patients

International FOP Association (IFOPA)

Find‐A‐Cure Benefit

• Founded in 1988 by Jeanie Peeper (Florida) • >500 members worldwide (50 countries) • Mission: – Fund research to find a cure for FOP – Support and education of individuals and families – Public awareness and advocacy

• Funds from family fundraising events and  donations • IFOPA supports research at ~$500,000/year (~75% of budget for FOP laboratory at U. Penn)

Santa Maria, CA

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BINGO for a Cure

FOP Summary • Rare, debilitating, genetic disease • Main clinical features: – Characteristic malformations of great toes – Rapidly appearing tumor‐like swellings that turn to  bone

• No effective treatment • Research support through IFOPA families • With recent research advances, probable clinical  trial of treatment in relatively near future Allentown, PA

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