1. Introduction to the Assessment of Skeletal Dysplasias
M Skae & M Kaleem
Bone & Calcium Disorders Annual Study Day
28th Sept’12

2. Introduction and overview
Assessment – before x-rays
The basics of radiological interpretation
Cardinal clues
X-rays
Who to involve – the MDT
Tools of the trade

3. Introduction
Skeletal dysplasias are conditions with generalised skeletal abnormalities
Usually associated with disproportionate short stature, normal intelligence
Incidence 1/5000 live births
Classified on clinical, radiological and molecular criteria and sometimes histology
Dys-plasia – abnormal – growth
Developmental problems: Specific areas – achondroplasia and hypochondroplasia; severe – Dgyvve-Melchior-Clausen and dysteosclerosis

4. Overview
2010 Nosology and Classification of Genetic Skeletal disorders
>450 different dysplasias, >220 genes
~100 have prenatal onset
remainder presenting in infancy or age 2-3years
In some conditions, features disappear with time and therefore are more difficult to diagnose retrospectively in adults.

5. Radiological diagnostic groupings
Achondroplasia group
Metatropic dysplasia group
Short-rib polydactyly (SRP) group
Diastrophic dysplasia (DD) group
Type II Collagenopathies
SEMDs
Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia group
Chondrodysplasia punctata (CDP) group
Metaphyseal chondrodysplasia (MCD)
Spondylometaphyseal dysplasia (SMD) group
Mesomelic dysplasia
Acromelic / acromesomelic group
Dysplasias with prominent membranous bone involvement – CCD
Bent bone dysplasia – Campomelic
Dysostosis multiplex group
Decreased bone density dysplasias – OI
Increased bone density dysplasias – osteopetrosis, pyknodysostosis
Defective mineralisation dysplasias – Hypophosphatasia
Craniotubular dysplasias – Pyle
Disorganised cartilagenous development – enchondrodysplasias
Osteolysis group
Patellar dysplasia – nail-patella syndrome

6. Assessment I - disproportion
Upper/lower segment ratio:
1.7 newborn
1.0 ages 2-8yrs
0.95 adult
Sitting height: ascertains trunkal shortening
Limb lengths:
Rhizomelia (humerus and femur)
Mesomelia (radius, ulna, tibia and fibula)
Acromelia (Hands and feet)
Body asymmetry
Spine: assess for scoliosis, kyphosis and lordosis
Normal
Rhizomelic
Mesomelic
Micromelic
Body asymmetry – ichtyosis, one sided body hypoplasia, clubbed feet, scoliosis, laryngeal stenosis, stippling of ankles and knees, elevated plasma sterol – Chondyplasia punctata (Conradi Hunerman type)

7. Assessment II – General examination
General examination: facial features, hair quality, dental health, nails
Systemic features: renal problems, cardiac abnormalities
Developmental history: Most normal
Family history
Ethnicity: CHH in Amish, SEMD with joint laxity in SA
Joint pain
Abnormal hair and susceptibility to infections – Cartilage-hair hypoplasia syndrome/McKusick Metaphyseal dysplasia
Renal problems – Schimke immuno osseus dysplasia; with asphyxiating thoracic dysplasia – Jeune or ATD syndrome
Developmental problems: Specific areas – achondroplasia and hypochondroplasia; severe – Dgyvve-Melchior-Clausen and dysteosclerosis
Congenital heart disease, polydactyly and dystrophic nails – Chondroectodermal dysplasia (Ellis van Creveld (EvC) syndrome
Nail patella syndrome – dystrophic nails, absent patella, short stature, bilateral iliac horns
Ear cysts and hitchhiker thumb – Diastrophic dysplasia

8. Assessment III - Radiology
Skeletal survey:
Skull AP & Lateral
Spine AP & Lateral
Pelvis AP
4 Limbs AP, occasional lateral Knee (assessment of patella)
Hands
Feet

9. Radiological assessment I
Epiphyseal dysplasia – small under ossified epiphyses
Metaphyseal dysplasia – widened, flared or irregular metaphyses
Diaphyseal dysplasia – cortical thickening or marrow space expansion or reduction

10. Radiological assessment II
Epiphyseal dysplasia
Metaphyseal dysplasia

11. Radiological assessment III
Vertebral (spondylo) abnormalities
Combinations:
Spondylo-epiphyseal dysplasia (SED)
Spondylo-metaphyseal dysplasia (SMD)
Metaphyseal-epiphyseal dysplasia (MED)
Spondylo-epiphyseal-metaphyseal dysplasia (SEMD)
SEMD – Pseudoachondroplasia (PSACH)

12. Question - Is it acquired?
Rule out acquired causes of bone problems:
Neuromuscular disorders
Chronic diseases – JIA
Poorly healed fractures
Metabolic bone problem
X-rays of a patient with dysplastic fibulas secondary to juvenile rheumatoid arthritis and previous high bilateral tibial osteotomies

13. Question II – Is it a common dysplasia? Kozlowski and Beighton
Achondroplasia
Cleidocranial dysostosis
Dactyly - Brachydactyly , Camptodactyly , Polydactyly , Syndactyly
Enchondromatosis (Ollier)
Fibrous dysplasia
usual form (Jaffe-Lichtenstein)
with skin pigmentation and precocious puberty (McCune-Albright)
Gaucher's
Hypophosphatemic rickets
Marfan's
Multiple hereditary exostoses
Neurofibromatosis
Osteogenesis imperfecta
Osteopetrosis, pyknodysostosis
Osteopoikilosis
INHERITANCE
Autosomal dominant (but 50% new mutations) FGFR3
CLINICAL FEATURES
Megalocephaly Short limbs
Prominent forehead Thoracolumbar kyphosis
Midfacial hypoplasia Short stature
RADIOLOGY
Diminishing interpeduncular distances between L1
and L5
COMPLICATIONS
Short stature Dental malocclusion
Hydrocephalus Repeated otitis media
4 stars = >1000 reports in the literature

14. Cardinal clues – cleidocranial dysostosis
Large head
Delayed suture closure
Hypertelorism, small face
Dental dysplasia – multiple teeth
Hypoplasia / aplasia of the clavicles

15. Cardinal clues – cartilage-hair hypoplasia
McKusick type metaphyseal chondrodysplasia
Short limbed dwarfism
Sparse hair
Autosomal recessive RMRP gene
T-cell and B-cell immunodeficiency
Dysplastic nails and brachydactyly
Notched incisors
Verne troyer the actor

16. Cardinal clues – Ellis van Creveld (chondroectodermal dysplasia)
Short stature, mesomelia
Narrow chest and short ribs
Polydactyly
Dysplastic nails
Dental abnormalities – missing teeth, lip fusion to gingiva
Cardiovascular abnormalities
AR – EVC1 & EVC2

17. Cardinal clues - Trichorhinophalyngeal syndrome (TRP) Type II / Langer-Giedion syndrome
Short stature
Unusual facies – long bulbous nose
Developmental delay
Cone epiphyses of the metacarpals
Bony exostoses especially distal tibia and ulna

18. Ear cysts
Hitchhiker thumb – shortened 1st metacarpal
Diastrophic dysplasia
Pierre Robin sequence – midface hypoplasia, high arched palate, micrognathia
Myopia
Hearing problems
Type II Collagenopathies

19. Cardinal clues - Osteopoikilosis
Dalmation disease – AD, LEMD3 & EXT1
small round or oval foci of bone sclerosis located in the trabecular bone
particularly in the pelvis, metaphyses and epiphyses of long bones, tarsals, and carpals

20. Cardinal clues - Melorheostosis
Dripping wax appearance
LEMD3 mutations
Linked to osteopoikilosis
Buschke-Ollendorff syndrome – dermatofibrosis lenticularis

21. Cardinal clues - osteopetrosis
Extra dense bone
‘Bone in bone’ appearance
Failure of normal osteoclast activity
May lead to marrow suppression – pancytopenia
Neural foramina stenosis

22. Cardinal clues - Enchondromatosis
Ollier’s syndrome
Not inherited
central expansile pattern or linear metaphyseal lucencies
5-30% malignant degeneration to chondrosarcoma
higher risk if associated with soft tissue haemangiomas (Mafucci's syndrome)

23. Who to involve - The MDT Geneticist Radiographer Metabolic bone doctor
Orthopaedic surgeon
Spinal surgeon
Physiotherapist
Occupational therapist

24. Tools of the trade A good atlas – Spranger, Brill and Poznanski
Warman et al. Nosology and classification of genetic skeletal disorders: 2010 revision. American Journal of Medical Genetics 2011 May;155(5): 943–968, May 2011
Alanay & Lachman. A Review of the Principles of Radiological Assessment of Skeletal Dysplasias
J Clin Res Pediatr Endocrinol December; 3(4): 163–178
Unger et al. A diagnostic approach to skeletal dysplasias. Paediatric Bone Disease 2003, 16. Elselvier Science.

25. Phone or e-mail a friend!
The European Skeletal Dysplasia network (ESDN) – usually accessed by the radiologists or genetists
The North-western Skeletal Dysplasia Group

26. SEMD – Pseudoachondroplasia (PSACH)
Anterior beaking of spinal processes with central protrusion, flared metaphyses, small dysplastic epiphyses - PSACH
SEMD – Pseudoachondroplasia (PSACH)

27. Vertebrae Double hump vertebrae – Dgyvve-Melchior-Clausen syndrome
Double hump – Dgyvve Melchior-Clausen syndrome
Coronal celfts – chondrodysplasia punctata, Kniest dysplasia
Humped vertebrae- spondyloepiphyseal dysplasia (SED) tarda – not apparent until adolescence
Double hump vertebrae – Dgyvve-Melchior-Clausen syndrome
Platyspondyly, ovoid vertebrae, gibbus, dysostosis multiplex, J shaped sella - MPS

28. Hand xrays Cone epiphyses of the metacarpals
Bony exostoses esp distal tibia and ulna
Trichorhinophalyngeal syndrome (TRP) Type II / Langer-Giedion syndrome
Osteolysis of distal phalanges
Pycnodysostosis

29. Hand xrays Proximal pointing of distal phalanges Bullet shaped
Hurlers disease (MPS)

30. Imaging Skeletal Dysplasias
Musa Kaleem (MBBS, MRCPCH, FRCR)
Imaging Skeletal Dysplasias

31. Constitutional disorders of bone
osteochondrodysplasias
dysostoses
Dysplasias (growth)
Osteodystrophies (texture)
Failure of gene expression
Phenotype usually continues to evolve
Defective bone formation due to a defect in blastogenesis
Remain static
do not spread to involve normal bones
Offiah et al; Pediatr Radiol 2003

32. Proliferating cartilage Hypertrophic cartilage
Zones
Resting
Proliferating cartilage
Hypertrophic cartilage
Provisional calcification
Ossification
20/04/2017

33. Genetics Skeletal Survey
Foetogram/ babygram AP
Lateral
Skull (AP & Lat)
Spine (AP & Lat)
Chest
Pelvis
One upper limb
One lower limb
Left hand (bone age)
Additional views
Lateral knee for assessment of patella)
Lateral foot (for calcaneum)

34. Radiological assessment – stepwise approach
Step 1 – assessment of disproportion
Spine
limb segments (rhizo/ meso/ acro)
Step 2 – assessment of epiphyses, metaphyses and diaphyses
Step 3 – assessment of bone density / texture

35. Radiological assessment (2)
Step 4 – search for other clues
Skull
Cranio-cervical junction
Spine
Ribs/ clavicles
Pelvis
Long bones
Hands and feet
Step 5 – Seek help from colleagues/ refer to textbook/ Electronic database
REAMS (radiol electronic database of malformation, syndromes and sk dysplasia
London dysmorphology database

36. Radiological assessment (3)
Epiphyseal dysplasia small/ under ossified/ irregular epiphyses
Metaphyseal dysplasia widened /irregular metaphyses
Diaphyseal dysplasia cortical thickening or marrow space changes

37. Radiological assessment (4)
Vertebral (spondylo) abnormalities
Combinations:
Spondylo-epiphyseal dysplasia (SED)
Spodylo-metaphyseal dysplasia (SMD)
Metaphyseal-epiphyseal dysplasia (MED)
Spondylo-epiphyseal-metaphyseal dysplasia (SEMD)

38. Radiological diagnostic groupings
Achondroplasia group
Metatropic dysplasia group
Short-rib polydactyly (SRP) group
Diastrophic dysplasia (DD) group
Type II Collagenopathies
SEMD
Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia group
Chondrodysplasia punctata (CDP) group
Metaphyseal chondrodysplasia (MCD)
Spondylometaphyseal dysplasia (SMD) group
Mesomelic dysplasia
Acromelic / acromesomelic group
Dysplasias with prominent membranous bone involvement – CCD
Bent bone dysplasia – Campomelic
Dysostosis multiplex group
Decreased bone density dysplasias – OI
Increased bone density dysplasias – osteopetrosis, pyknodysostosis
Defective mineralisation dysplasias – Hypophosphatasia
Craniotubular dysplasias – Pyle
Disorganised cartilagenous development – enchondrodysplasias
Osteolysis group
Patellar dysplasia – nail-patella syndrome
Alanay Y, Lachman RS et al; J Clin Res Pediatr Endocrinol: 2011

39. DIASTROPHIC DYSPLASIA
Related to MED, atelosteogenesis, achondrogenesis

41. Radiological hints to diagnoses
Skull
Changes in density, size and shape
Wormian bones OI
Cleidocranial dysostosis
Pyknodysostosis
Craniosynostosis
Crouzon’s/ Pfeiffer’s
Skull base/ midface hypoplasia
Basilar invagination

42. Achondroplasia
Large skull with fronto-occipital bossing, narrow skull base and midface

43. Mucopolysaccharidosis
This represents our overall minimum incidence of MPS and related diseases of 1:26,000, with specific incidences as follows: Hurler: 1:115,000 Hunter: 1:166,000 Sanfilippo: 1:89,000 Morquio: 1:220,000
The mucopolysaccharide diseases are classified as MPS I-IX. They are named after the doctor who first described them:
Hurler (MPS IH) alpha-L-iduronidase deficiency
Hurler Scheie (MPS IHS) alpha-L-iduronidase deficiency (formerly MPS V)
Scheie (MPS IS) alpha-L-iduronidase deficiency
Hunter (MPS II) alpha-L-iduronidase-2-sulphate-sulphatase deficiency
Sanfilippo (MPS III) four distinct enzyme abnormalities, same clinical patterns
Morquio (MPS IV) A galactosamine-6-sulphate sulphatase
Morquio (MPS IV) B beta-galactosidase
Maroteaux Lamy (MPS VI) N-acetyl galactosamine-4-sulphatase deficiency
Sly (MPS VII) beta-gluconidase deficiency
MPS IX hyaluronidase deficiency.

44. Generalised reduced density: Osteogenesis Imperfecta (OI)
OI in a neonate
Dominant mutations COL1A1, COL1A2 :defects in type I collagen
Lots of subtypes
AD: I and IV are least severe
AR III more severe
AD II lethal at birth, most of these are new mutations
Features :
thin cortices
decreased ossification of skull base,
wormian bones along the lambdoid suture
Multiple fractures (lethal neonatal type)
Lethal type II:
Skull features, General osteopenia, Thick ribs with beading and cont #, Short, thick crumpled bones
Glass R B J et al. Radiographics 2004;24:

45. Wormian bones… General Considerations: Wormian bones
Accessory bones within a suture of the skull
Most often lambdoid suture
Normal variant : up to 80% of Asian
Males > females
Pathological when > 10 or large
A larger, single, centrally located intra sutural bone at the junction of the lambdoid suture and sagittal suture is called the os inca
They are named after Ole Worm, a Danish anatomist who described them
From radiopedia.org

46. Two recessive types of OI, Types VII and VIII, were identified in 2006
Two recessive types of OI, Types VII and VIII, were identified in Unlike the dominantly inherited types, the recessive types of OI do not involve mutations in the type 1 collagen genes.
These recessive types of OI result from mutations in two genes that affect collagen
the cartilage-associated protein gene (CRTAP)
the prolyl 3-hydroxylase 1 gene (LEPRE1)
Recessively inherited OI has been discovered in people with lethal, severe and moderate OI. There is no evidence of a recessive form of mild OI. Recessive inheritance probably accounts for fewer than 10 percent of OI cases.

47. OI

48. Generalised reduced bone density: HYPOPHOSPHATASIA
Heterogenous disorder
Low or absent alk phos due to lack of tissue non specific alk phos
AR: cong form, lethal
AD: milder
Decreased/absent ossification of calvaria
Poor ossification of vertebrae or islands of deficient bone

49. Increased density: osteopetrosisAR
Benign vs malignant forms
Presents with infection/ cranial nerve palsies

50. Increased density: generalised
Pycnodysostosis:
Thick calvarias, delayed closure: wide lambdoid sutures and fontanelles, multiple wormian bones
Other features:
Short limbs
Hypoplasia of mandible
Obtuse mandibular angle
Segmentation failure C1/2 L/S1
Hypoplastic clavicles-narrow or resorption of the lateral ends
Slender diaphysis
**Acro osteolysis of the terminal phalanges
Pycnodysostosis

51. Frontometaphyseal dysplasia
Related to FNLA gene.
xlinked dominant:
prominence of the supraorbital ridges, restricted thoracic expansion, sternal deformity and joint contractures
More severe in male, variable in female
Sclerosis is limited to the frontal bone and the skull base
Glass R B J et al. Radiographics 2004;24:

52. Spine Odontoid hypoplasia/ atlanto-axial subluxation
Kyphoscoliosis (gibbus)
Pedicles (length/ interpediculate distance)
Vertebral body shape abnormalities
Platyspondyly
Bullet shaped vertebrae/ vertebral beaking
Scalloped vertebrae
Humps
Cleft vertebrae (sagittal/ coronal)

53. MPS – dysostosis multiplex
Dysostosis multiplex is an autosomal recessive disorder that results in the intralysosomal accumulation of a variety of complex carbohydrates, all of which have similar skeletal manifestations. The skull is enlarged with thick diploe and J-shaped sella tursica. In the chest, the ribs are oar-shaped, the clavicles are wide and the scapulae are thick. Vertebral bodies are often ovoid with anterior hook-like projections. The inferior ilia are consticted and the iliac wings are flared. The long tubular bones show irregular diaphyseal modeling, submetaphyseal constriction and shortening. The short tubular bones demonstrate metaphyseal widening and epiphyseal dysplasia; the proximal 2nd through 5th metacarpal bones are tapered. Overall bones are demineralized with coarse trabeculation.

54. Achondroplasia
1.Achondroplasia and pseudoachondroplasia are clinically and genetically distinct phenotypes that are among the most common human disorders resulting in short stature. Both are inherited as autosomal dominant conditions. Achondroplasia, the single most common form of human dwarfism, results in most cases from one of two very specific mutations in the gene encoding fibroblast growth factor receptor 3 (FGFR3). Pseudoachondroplasia is caused by a variety of mutations in the gene encoding cartilage oligomeric matrix protein (COMP). Both disorders are characterized by short-limb dwarfism, in which the affected person's arms and legs are relatively short compared to the height of the trunk. Disorders with clinical, radiographic, and molecular features in common with achondroplasia include hypochondroplasia, thanatophoric dysplasia (TD), and severe achondroplasia with developmental delay and acanthosis nigricans (SADDAN). Similarly, pseudoachondroplasia and multiple epiphyseal dysplasia (MED) are related.

55. CDPX2
Chondrodysplasia
Punctata (x-linked)

56. SED Tarda Short trunk Humped vertebrae Proximal epiphyseal
irregularities

57. dd: Chondrodysplasia Punctata Atelosteogenesis Kniest dysplasia
Short rib polydactyly OI
Radiopaedia.org
Radiopaedia.org

58. Pelvis and Lower limbs Iliac shape / horns Pubis/ ischium ossification
Sacro-sciatic notches
Acetabulum orientation and shape
Femoral head abnormalities
Delayed ossification
Abnormal ossification
Metaphyseal irregularities
Shortening of long bones
Layered patella
Multiple calcaneal ossifications

59. Newborn with abnormally soft head
Hypophosphatasia
Heterogenous disorder
Low or absent Alk Phos due to lack of tissue non-specific alk phosphatase
AR: congenital form (lethal)
AD: milder
Decreased/absent ossification of calvaria
Poor ossification of vertebrae or islands of deficient bone
Abnormal metaphyses

60. 11 month old - pancytopaenic
Infantile osteopetrosis
Diffuse osteosclerosis with a “bone-in-bone” appearance in the iliac bones and the femora
Irregular femoral metaphyseal ossification
Comment: The bone-in-bone appearance reflects fluctuating disease activity. The innermost bone is the size and shape of a neonatal bone. The metaphyseal appearances may resemble rickets (‘osteopetrorickets’)
7 months old with marrow failure

61. 1 month post BMT
2 months
10 months

62. 2 day old with short limbs
Achondroplasia
Rounded iliac wings with horizontal acetabula and narrow sacrosciatic notches
Narrowing of the lower lumbar interpedicular distance
Upper femoral metaphyses are broad and lucent
The pelvic appearances (‘trident’ acetabulum) are seen in other conditions, but the combination, with the spinal changes indicates achondroplasia.

63. Neonate with severe respiratory distress and short limbs
Thanatophoric dysplasia (type 1)
Small iliac bones with small sacrosciatic notches
Broad ischial and pubic bones
Severe platyspondyly
Short curved femora
The pelvic appearances are similar to, but more severe than those seen in achondroplasia, as well as those in asphyxiating thoracic dystrophy and related disorders.

64. 1 year old with short limbs and large joints
Metatropic dysplasia
Crescent shaped iliac crests with short inferior portions of the iliac bones
Low anterior iliac spines and horizontal acetabula
The proximal femora show metaphyseal broadening (‘battle-axe’ appearance)
Small femoral epiphyses
Lumbar platyspondyly
Affected individuals may have a tail-like appendage of the sacrum.

65. 3 year old with short stature and facial dysmorphism
Mucopolysaccharidosis type IV (Morquio disease)
Narrowing of the inferior portions of the iliac bones, with shallow acetabula
Irregular ossification of the femoral epiphyses
Lumbar platyspondyly
The iliac and acetabular morphology is common to all mucopolysacchharidoses. The platyspondyly and epiphseal changes suggest Morquio disease
3 yr old with short stature and facial dysmorphism

66. 11 yr old with painful hips
Diagnosis: Multiple epiphyseal dysplasia
Femoral capital epiphyses are symmetrically flattened
The acetabula are mildly shallow
Normal metaphyses and tubular bones
Varying degrees of platyspondyly and end-plate irregularity
MED results in progressive joint deformities and early degenerative changes. The phenotype may be due to >5 different gene mutations

67. Skeletal dysplasia Daunting task!
“there are known knowns. These are things we know that we know. There are known unknowns, that is to say, there are things that we know we don’t know. But there are also unknown unknowns. These are things we don’t know we don’t know”
Donald Rumsfeld, US Ex-Secretary of Defence

68. Thank you