Introduction to Skeletal Dysplasias

Genetics Fellow Teaching June 2019

Transcript

1. Introduction to Skeletal Dysplasias Prof Andreas Zankl Bone Dysplasia Clinic The Children’s Hospital at Westmead
2. Genetic disorders affecting skeletal development What are Skeletal Dysplasias?
3. phases of skeletal development skeletal patterning skeletal growth skeletal homeostasis
4. disorders of skeletal patterning e.g. Fuhrmann syndrome
5. disorders of skeletal patterning e.g. spondylocostal dysostosis
6. disorders of skeletal growth many forms of dwarfism
7. disorders of skeletal homeostasis
8. Skeletal Dysplasias • individually rare • group prevalence at least 1:5000 individuals1 • ca. 2’000’000 cases worldwide • ca. 5000 in Australia 1. Wynne-Davies R,:Bone Joint Surg Br 1985, 67:133–137. 2. Stevenson DA, Am J Med Genet 2012, 158A:1046–1054.
9. Complex Medical Problems • skeletal deformities • early arthritis • bone fragility • neurological damage • respiratory failure • …
10. Bone Dysplasia Clinic Multidisciplinary care • Genetics • Endocrinology • Rehabilitation Medicine • Physio/OT • Orthopaedics
11. nd Mundlos: Genetic Disorders of the Skeleton 457 good models to study bone and cartilage biology cleidocranial dysplasia osteogenesis imperfecta osteoporosis-pseudoglioma osteopetrosis juvenile Paget disease metaphyseal anadysplasia osteoporosis-pseudoglioma Pfeiffer syndrome MCD Schmid type acrocapitalfemoral dysplasia Achondroplasia Campomelic dysplasia spondyloepiphyseal dysplasia MCD Jansen type
12. Knowledge from rare diseases can be applied to common diseases • mutations in cathepsin K cause pycnodysostosis • Cathepsin K is a protease involved in matrix degradation by osteoclasts • Blocking cathepsin K activity should increase bone density • Cathepsin K inhibitor (Odanacatib) as a treatment for osteoporosis • (failed in clinical trials due to side effects)
15. Morquio Syndrome
16. Classification 1878 Description of “Achondroplasia” 1929 Description of “Morquio Syndrome” 1970 First International Nosology of 
 Constitutional Diseases of Bone 2010 7th Revision of the Nosology: 456 disorders 2015 8th Revision: 436 disorders 1970 1929 1878 2010 2015
17. knowing the diagnosis is important • different recurrence risks • different types of complications • different management • specific treatments
19. Diagnosis of Skeletal Dysplasias • History • Physical exam • Radiographs • Investigations • Genetic testing
20. onset and progression of symptoms: • prenatal: TD, ACG, OI, SRP • birth: ACH, SEDC • first years of life: PSACH, HCH, CHH • after 3 years: MED, brachyolmia, SED tarda → important to have good growth charts! history
21. history associated medical problems: • cleft palate, myopia, hearing loss: type II collagenopathies • intellectual impairment: LSD, Dyggve-Melchior-Clausen • hematological abnormalities: CHH, Shwachman
22. family history • “short stature” • “arthritis” • “joint pain”
23. Grebe Dysplasia Brachydactyly C
25. Consanguinity • Amish • Ellis van Creveld • cartilage-hair hypoplasia • Finnish • cartilage-hair hypoplasia • diastrophic dysplasia • Puerto Rican • Jarcho-Levin
26. physical examination US LS rhizo- meso- acro-
27. short trunk vs short limbs
28. other clues Nail-Patella Syndrome Diastrophic Dysplasia
29. Radiographic Evaluation Rule #1: You shall not diagnose without a skeletal survey
30. Basic Skeletal Survey • skull lateral • thorax AP • spine lateral • pelvis AP (including lower spine and proximal femurs) • knees AP • hand AP (including wrists)
31. Extended Skeletal Survey • skull AP • spine AP • knees lateral • upper extremity AP • lower extremity AP • cervical spine lateral (extension, flexion)
32. Skeletal Survey ≠ Skeletal Survey
33. what to look for • bone structure • timing of ossification • primary sites of involvement • bone shape • specific signs • the big picture
34. osteopetrosis osteolysis bone structure
35. osteopoikilosis melorheostosis bone structure
36. timing of ossification always record the age when xrays were taken!
37. hypoplastic dens
 (pseudoachondroplasia) unossified vertebral bodies
 (opsismodysplasia,10 years) ossification delay
38. cervical spine problems
39. fro 3 yrs, girl, SEDC Extension Flexion
40. primary site of involvement metaphyseal- epiphyseal- spondylo-
41. spondyloepiphseal dysplasia congenita ≠ spondyloepiphyseal dysplasia tarda (X-linked) ≠ spondyloepiphyseal dysplasia tarda (AR)
42. mucopolysaccharidosis achondroplasia shape
43. shape “wafer-thin” Thanatophoric dysplasia I “hook-shaped” mucopolysaccharidoses “anterior tongue” pseudoachondroplasia
44. “interpedicular narrowing” (Achondroplasia/Hypochondroplasia)
45. specific signs
46. french telephone receiver sign
 (thanatophoric dysplasia type 1)
47. monkey wrench sign Desbuquois Dysplasia
48. “Schneckenbecken” (snail pelvis) dysplasia
49. “angel-shaped” phalanx angel-shaped phalango-epiphyseal dysplasia (ASPED)
50. (cartilage-hair hypoplasia, Jeune S., tricho-rhino-phalangeal S., ...) cone-shaped epiphyses
51. “tomb stone” phalanges atelosteogenesis III
52. Wormian bones • osteogenesis imperfecta • cleidocranial dysplasia • pyknodysostosis • Down syndrome
53. “iliac horns” (nail-patella syndrome)
54. (spondylocostal dysostosis) “pebble beach sign”
55. coathanger sign (paternal UPD 14)
56. “double-layered patella” (autosomal recessive MED)
57. The Big Picture
60. C D J-shaped sella
61. tapering of proximal metacarpals bullet shaped phalanges
62. broad clavicles broad ribs
63. D dysostosis multiplex in the skull. (A) normal J-shaped sella turcica, (B) ab the skull of a patient with normal diploic plates and mildly abnormal J-shap loic plates and severe J-shaped sella (arrows) A B x in the thorax. Radiographs showing (A) a normal chest and (B) a chest of an MPS patient showing cles (arrows). en characterized by apering of the ilea the ileum merging of region. Inferior isorders. A newly The hands of MPS patients typically show proximal- ly pointed metacarpals. Metacarpals can be short and thick with thin cortices, even if proximal pointing is not present. Nonspecific findings include hypoplastic and irregular carpal bones, and irregularlyshaped tarsal t a critical aspect in MPS (partic- e if the spinal cord is compressed, result. MRI is more appropriate l cord alterations. hape of vertebral bodies are very attened and rounded vertebrae mbar level the vertebral body can terosuperior corner and, as a con- ongation of the anteroinferior one, ay in an “anterior beaking” aspect. nterior corners occurs, the vertebral LSD
64. age-dependent changes birth 1 year 4 years 5 years 14 years
65. age-dependent changes 12 days 4 months 9 months 5.5 years
66. Further Investigations
67. Serum Ca, Ph, PTH, Vitamin D • mostly to exclude other causes (e.g. rickets) • normal in most bone dysplasias
68. Full Blood Count • Cartilage-Hair Hypoplasia • Shwachmann syndrome
69. Exclude Lysosomal Storage Disorders • quantitative analysis of urinary GAGs • qualitative analysis of urinary GAGs 
 (electrophoresis, now Mass-Spec) • enzyme assays
70. Histology
71. Genetic Testing • Lots of options • Clinical/radiographic review helps targeting the testing • Clinical/radiographic review helps interpreting the results
76. please contact me for Research Whole Genome Sequencing Undiagnosed Bone Dysplasia after previous testing (including structural variants, bone specific filters and more…)
77. Summary • getting the right diagnosis is important • Clinical-radiographic evaluation still important
78. Bone Dysplasia Consultation Service Please send me: • clinical summary • skeletal survey on CD
79. • for ongoing management Bone Dysplasia Clinic
80. please contact me for Research Whole Genome Sequencing Undiagnosed Bone Dysplasia after previous testing (including structural variants, bone specific filters and more…)
81. Thanks for Listening! Contact me: andreas.zankl@sydney.edu.au Download slides: https://tinyurl.com/skeldys