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

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

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

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.

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

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)

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

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

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

Radiological assessment II Epiphyseal dysplasia Metaphyseal dysplasia

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)

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

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

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

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

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

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

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

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

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

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

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)

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

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. 2011 December; 3(4): 163–178 Unger et al. A diagnostic approach to skeletal dysplasias. Paediatric Bone Disease 2003, 16. Elselvier Science.

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

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

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

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

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

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

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

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

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)

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

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

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

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

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

DIASTROPHIC DYSPLASIA Related to MED, atelosteogenesis, achondrogenesis

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

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

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.

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;24:507-522

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

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 2006. 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.

OI

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

Increased density: osteopetrosis AR Benign vs malignant forms Presents with infection/ cranial nerve palsies

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

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;24:507-522

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)

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.

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.

CDPX2 Chondrodysplasia Punctata (x-linked)

SED Tarda Short trunk Humped vertebrae Proximal epiphyseal irregularities

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

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

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

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

1 month post BMT 2 months 10 months

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.

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.

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.

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

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

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

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