Imaging in skeletal dysplasia based on families

Imaging in skeletal dysplasia

1. Skeletal Dysplasia Familie S Moderator : Dr SANJU (assistant professor ) Presentation by Dr Navya ,PGY2 Department of radio-diagnosis MMC,Khammam

2. Introduction to Skeletal Dysplasia Families and Pattern Recognition Skeletal dysplasias have been grouped into “families” on the basis of the radiologic manifestations and genetic causes They all share a core radiologic pattern with minor differences between individual disorders . Dysostosis multiplex family (mucopolysaccharidosis [MPS], mucolipidosis, and oligosaccharidosis) Achondroplasia family Multiple epiphyseal dysplasia (COMP) family Skeletal ribosomopathies (metaphyseal dysplasias) Type II collagenopathies – SEDC group and Stickler- Kniest group Metatropic dysplasia (TRPV4) family Diastrophic dysplasia (DTDST) family Larsen dysplasia family ( filaminopathy B) 9. Skeletal ciliopathies 10. Punctata family Osteogenesis imperfecta group Osteopetrosis group

3. Dysostosis multiplex family Clinical and genetic features Dysostosis multiplex family comprises a heterogeneous group of lysosome storage disease, including MPS, mucolipodosis (ML), and oligosaccharidosis , that are due to the accumulation of partially degraded complex carbohydrates as a result of lysosomal enzyme deficiency . Most patients are initially asymptomatic but develop physical and mental disabilities in early childhood . Regardless of the type of molecules, their accumulation results in the same lysosomal dysfunction that causes the common skeletal changes of dysostosis multiplex . Some disorders have disease- specific skeletal changes related to the property of accumulated m olecules . Neonatal forms of dysostosis multiplex (e.g., I-cell disease, GM1 gangliosidosis) show severe secondary hyperparathyroidism and stippled epiphyses

4. Dysostosis multiplex family Hurler, Hunter, and Morquio syndromes (different types of MPS ) share common skeletal changes termed dysostosis multiplex — eg, flared ilia, a wineglass appearance of the inner pelvic rim , constriction of the proximal fem urs with coxa valga , hooked vertebral bodies , proximal metacarpal pointing, and bullet- shaped phalanges . Morquio syndrome uniquely show s platyspondyly (flat vertebral bodies) and prominent epiphyseal dysplasia . Constriction of the proximal femora with coxa valga Proximal metacarpal pointing and bullet- shaped phalanges Hooked vertebral bodies Flared ilia and wine glass appearance of the inner pelvic rim Constriction of the proximal femora with coxa valga Proximal metacarpal pointing and bullet- shaped phalanges Hooked vertebral bodies Flared ilia and wine glass appearance of the inner pelvic rim Constriction of the proximal femora with coxa valga Proximal metacarpal pointing and bullet- shaped phalanges Hooked vertebral bodies Flared ilia and wine glass appearance of the inner pelvic rim Epiphyseal dysplasia A young child A child Hurler disease (MPS IH) Hunter disease (MPS IIA) Morquio disease (MPS IV) Platyspondyly A young child

5. Radiologic approach 1 st step : Common skeletal features of Dysostosis multiplex family: a heterogeneous group of lysosome storage diseases dysostosis multiplex include: Macrocephaly , thick calvaria , J- shaped sella (  ) Oar- shaped ribs , wide clavicles Hooked vertebral bodies (  ) , posterior vertebral scalloping Flared iliac wing Overconstriction of the distal ilia (“wine glass appearance”) Coxa valga Metaphyseal constriction and diaphyseal expansion Proximal metacarpal pointing , bullet- shaped short phalanges 2 nd step : Identification of differences in severity and distinctive skeletal changes: Severity: Hurler > Hunter > Scheie Platyspondyly and epiphyseal deformity in Morquio syndrome Epiphyseal dysplasia in ML3 and Maroteaux - Lamy Secondary HPT and stippled epiphyses in neonatal forms of dysostosis multiplex I cell disease

6. Achondroplasia family: a group of allelic disorders related to FGFR3 gene Achondroplasia family comprises a group of allelic disorders that are due to gain- of- function mutations of the FGFR3 gene, including thanatophoric dysplasia (TD), achondroplasia (ACH), and hypochondroplasia (HCH) in decreasing order of severity . FGFs- FGFR3 signaling inhibits proliferation of chondrocytes and synthesis of cartilage matrix; different FGFR3 mutations cause variable degrees of impairment of endochondral bone formation and lead to the same pattern of skeletal changes but with different severit ies. TD, ACH, and HCH have disease- specific FGFR3 mutations; thus, they show a homogeneous skeletal phenotype. Intermediate phenotypes are rare . Patients with the three disorders manifest with short- limb short stature; TD is perinatally lethal owing to thoracic hypoplasia as a result of severe rib shortening .

7. Thanatophoric dysplasia, achondroplasia, and hypochondroplasia (FGFR3-related bone dysplasias) share common skeletal changes in decreasing order of severity — eg, a narrow thorax , caudally decreased interpediculate distances , vertebral deformity, small iliac bones with short sciatic notches , ovoid lucency in the proximal femora , and short and broad tubular bones with metaphyseal cupping/flaring . Extremely narrow thorax Small iliac bones with trident appearance Posterior bowing of the tibia/fibula Disproportionately large skull “Bullet- shaped” flat vertebral bodies and narrow spinal canal Narrow, bell- shaped thorax Absence of normal increase in caudal interpediculate distances Ovoid lucency in the proximal femora Small iliac bones with short sacrosciatic notches and “trident” acetabula Short long bones with metaphyseal cupping Disproportionately large skull Mildly narrow thorax long bones Absence of normal caudal interpediculate widening Small iliac bones with short sacrosciatic notches Ovoid lucency in the proximal femora Mild shortening with metaphyseal flaring of Thanatophoric dysplasia Decreased caudal interpediculate distances Achondroplasia Family (FGFR3- related bone dysplasias) Milder Severe platyspondyly Milder Ovoid lucency of the A stillbirth proximal femur Severe shortening of long bones with metaphyseal cupping “French telephone receiver femur” (bowed, short femur) A neonate Achondroplasia Hypochondroplasia A neonate

8. Radiologic approach 1 st step : Common radiologic findings include: Shortening of the skull base Deformity of the vertebral bodies Narrowing of the caudal interpediculate distances Iliac hypoplasia Ovoid radiolucency of the proximal femora Metaphyseal cupping and flaring with metaphyseal spur of tubular bones 2 nd step : The three disorders show different severity and unique findings TD shows thoracic hypoplasia with severely shortened ribs and severe platyspondyly (flattening of vertebral bodies) TD type 1 shows French telephone receiver– like bowing of fem urs ; type 2 show s clover leaf skull deformity and straight fem urs ACH is the prototype of this family; limb shortening and spondylar changes are much milder than those of TD. " Trident” hand HCH show s only narrow interpediculate distance, iliac hypoplasia, and radiolucency of proximal femur ACH “Trident” hand

9. This heterogeneous group of disorders show predominant shortening of the acromelic ( hands and feet) and mesomelic (forearms and lower legs) segments. Acromesomelic dysplasia type Maroteaux is characterized by acromesomelic shortening with generalized brachydactyly, bowing of the radius and ulna, and platyspondyly Leri- Weill dyschondrosteosis , by mesomelic shortening with Madelung deformity of the forearm (bowed radius, medial tilting of the distal radial end, and distal ulnar subluxation); Albright hereditary osteodystrophy (a clinical manifestation of pseudohypoparathyroidism or pseudo-pseudohypoparathyroidism) , by brachydactyly (metacarpal shortening , particularly of the ulnar digits) and distal phalangeal shortening , particularly of the first digit . Mesomelic and acromelic dysplasias: a group of disorders with primary acro/mesomelic involvement

10. Mesomelic shortening Severe brachydactyly, more prominent than achondroplasia, associated with cone- shaped epiphyses Madelung deformity: V- shaped wrist joint Dorsal subluxation of the distal ulna Bowed radius Shortening of ulnar metacarpals and distal phalanges Periarticular soft - tissue calcifications Acromesomelic dysplasia type Maroteaux NPR2 mutation Absence of caudal interpediculate narrowing (vs achondroplasia) Mesomelic and acromelic dysplasias: a group of disorders with primary acro/mesomelic involvement Mild platyspondyly Musculoskeletalkey.com Mesomelic shortening and bowed radius/ulna An 11- year- old male A 13- year- old female Leri- Weill dyschonrosteosis SHOX deletions or mutations Shortening of fibular metatarsals and distal phalanges A 12- year- old female Albright hereditary osteodystrophy GNAS mutations

11. Multiple epiphyseal dysplasia family (COMP- related bone dysplasias) Pseudoachondroplasia MED (mild) Shortened short tubular bones with small epiphyses and cupped metaphyses Small epiphyses with cupped metaphyses Small, round capital femoral epiphyses Platyspondyly with biconvex vertebral bodies Small, round capital femoral epiphyses Small, irregular epiphyses with cupped metaphyses Shortened short tubular bones with small epiphyses MED (severe) Mild biconvexity of vertebral bodies Mild biconvexity of vertebral bodies Mildly small epiphyses Milder Pseudoachondroplasia (PsACH) and multiple epiphyseal dysplasia (COMP- related MED) share the same pattern of abnormal epiphyseal ossification — i e, delayed epiphyseal ossification with small, round, irregular epiphyses . However, PsACH (the severest phenotype of this group) shows prominent spondylar dysplasia and metaphyseal dysplasia . A young child Severer A young child A child

12. Clinical and genetic features Multiple epiphyseal dysplasia (MED) encompasses a diverse group of disorders characterized by abnormal epiphyseal ossification . MEDs are caused by mutations in genes of cartilage matrix proteins — eg, COMP (cartilage oligomelic protein gene), MATN3 (matrilin 3), and type IX collagen genes ( COL9A2, COL9A3, COL9A1 ). COMP- MED is the most common. The severest end of COMP- MED is pseudo- achondroplasia (PsACH) . MED manifests with postnatal short stature with short limbs. Short stature is severe in PsACH, moderate in CO M P- MED, and mild in other MEDs; abnormal epiphyseal ossification of MED evolves into premature degenerative joint disease . Multiple epiphyseal dysplasia family: COMP- related dysplasias and other MEDs

13. Radiologic al approach 1 st step : MED is characterized by abnormal (delayed, irregular) epiphyseal ossification 2 nd step :The pattern of abnormal epiphyseal ossification is different among MEDs Small, round epiphyseal ossification in COMP- MED Small, flat epiphyseal ossification with longitudinal metaphyseal striations in MATN3- MED Normal capital femoral epiphyses and peripheral epiphyseal dysplasia (such as knees) in type IX collagen – related MED These differences are best seen in preadolescent ages, and a radiologic differential diagnosis of these subtypes may be impossible in adulthood PsACH is associated with severe spondylar and metaphyseal dysplasias MATN3 - MED COL9A2 - MED COMP - MED Small, ROUND capital femoral epiphyses Small, FLAT epiphyses Normal hips Abnormal knee Multiple epiphyseal dysplasia family: COMP- related dysplasias and other MEDs

14. Skeletal ribosomopathies: a group of metaphyseal dysplasias with ribosome dysfunction Impairment of ribosome biogenesis (a global process that occurs in all cells) causes multi system disorder; mutations in certain genes of ribosomal molecules predominantly affect the skeleton . Shwachman- (Bodian)- Diamond syndrome (SBDS) is commonly caused by SBDS mutations and rarely by mutations of other disease- causing genes recently discovered; SBDS manifests with generalized metaphyseal dysplasia associated with exocrine pancreatic dysfunction and bone marrow failure (neutropenia). The bone marrow failure may evolve into myelodysplastic syndrome and acute myeloid leukemia with age . Cartilage- hair hypoplasia (CHH) is caused by RMRP mutations and manifests with metaphyseal dysplasia accompanied by sparse and fine hair , and defective T- cell and/or B- cell mediated immunity. The immunodeficiency may cause lymphoma later . The severe phenotype of RMRP mutations is termed anauxetic dysplasia; new genes for aneuxetic dysplasia have been recently discovered . Clinical and genetic features

15. Metaphyseal dysplasia most conspicuous in the hips Mildly narrow thorax Metaphyseal dysplasia more conspicuous in the knees A 1- year- old A 2- year- old female Brachydactyly with metaphyseal cupping Shwachman- Diamond syndrome Cartilage hair hypoplasia Minimal brachydactyly Skeletal ribosomopathies, including Shwachman- Bodian- Diamond syndrome (SBDS) and cartilage hair hypoplasia (CHH), manifest with metaphyseal dysplasia. Metaphyseal dysplasia of the hip is conspicuous in SBDS, while that of the knee is conspicuous in CHH. A narrow thorax is prominent in SBDS, while brachydactyly is distinctive in CHH . Skeletal ribosomopathies (metaphyseal dysplasias)

16. Radiological approach 1 st step : The skeletal manifestation 2 nd step : The location s of severest Skeletal ribosomopathies: a group of metaphyseal dysplasias with ribosome dysfunction of ribosomopathies is metaphyseal dysplasia = rickets-like metaphyseal changes (splaying, cupping, and irregularity). Contrary to rickets with diffuse osteopenia (osteomalacia) (  ), bone mineralization is normal in ribosomopath i es; metaphyseal dysplasia has a postnatal onset . involvement are different between SBDS and CHH SBDS shows severe metaphyseal dysplasia of the proximal fem urs ; severely affected ribs lead to thoracic hypoplasia . CHH shows metaphyseal dysplasia that is more severe in the knee than in t he hip; severe brachydactyly with delta- shaped metaphyseal deformity is a hallmark of CHH . Anauxetic dysplasia manifests with extremely severe short stature with early onset of metaphyseal dysplasia Shwachman- Diamond synd. Cartilage hair hypoplasia Rickets Anauxetic dysplasia

17. Other metaphyseal dysplasias Metaphyseal dysplasia Schmid type COL10A1 mutations Metaphyseal anadysplasia MMP9/MMP13 mutations Metaphyseal dysplasia in infancy Metaphyseal changes with bowing of the femur and tibia 6 month Resolution of metaphyseal changes over time Other metaphyseal dysplasias also show rickets-like metaphyseal irregularities. In addition, metaphyseal dysplasia Schmid type shows coxa vara and large capital femoral epiphyses. Metaphyseal anadysplasia is unique in that the metaphyseal changes are most conspicuous in the neonatal period through infancy and resolve spontaneously by 6 years of age. Metaphyseal dysplasia Jansen type is the most severe type of metaphyseal dysplasia , with severe widening of the growth plate and enlarged round epiphyses . 12 month Coxa vara and coxa magna 6 month follow up Metaphyseal dysplasia Jansen type PTHR1 mutations Metaphyseal dysplasia with severe widening of the growth plate and large epiphyses A young child A young child

18. Clinical and genetic features Type II collagen is the major collagen in the cartilage matrix . Abnormalities in the COL2A1 lead to a group of skeletal dysplasias, collectively known as type II collagenopathies, one of the most common bone dysplasia families . The major clinical feature of these dysplasias is short stature predominantly caused by a short trunk and short neck; mid- facial hypoplasia, micrognathia, and cleft palate are common associations . Type II collagen is also an essential component of the vitreous body of the eyes and inner ears; affected individuals often exhibit vitreoretinal degeneration leading to severe myopia and retinal detachment, as well as sensorineural or mixed hearing loss . Type II collagenopathies : a group of allelic disorders related to abnormal type II collagen

19. The s pondyloepiphyseal dysplasia congenita ( SEDC) family is a subgroup of of type II collagenopathies that forms a continuous radiographic spectrum and is characterized by delayed ossification of juxta truncal bones ( vertebral bodies , pelvic bones , and epi metaphyses of long bones , especially of the proximal segment) . V ertebral ossification ranges from total absence to modest modification (pear - shaped vertebral bodies); pubic ossification is usually absent, and ischial ossification may be missing . T he fem u r s and humeri may show metaphyseal ossification defect, but long bones usually show only shortening with delayed epiphyseal ossification, especially of the proximal fem urs. A stillb orn Small ilia with concavities of the inner and inferior margin Severe shortening of long bones with striking metaphyseal cupping Absent ossification of the pubic and ischial bones Small ossification of the vertebral bodies. Ossification of the cervical vertebral bodies and sacrum is absent Moderate shortening of long tubular bones The ilia and ischia are ossified, while the ossification of the pubic bones is absent A stillborn Short and broad ilia with horizontal acetabular roof and absent pubic ossification Long tubular bones show delayed epiphyseal ossification, shortening, and mild metaphyseal broadening Severer Severer Achondrogenesis type 2 Hypochondrogenesis Near ly complete absence of spinal ossification A neonate Spondylar dysplasia with dorsally wedged, pear- shaped vertebral bodies Type II collagenopathies (1) – SEDC family Spondyloepiphyseal dysplasia congenita

20. The other subgroup of type II collagenopathies is Stickler- Kniest dysplasia family, which is radiologically characterized by dumbbell - shaped deformity of long bones and spondylar dysplasia . Kniest dysplasia show s severe dumbbell deformity and platyspondyly with coronal clefts; Stickler dysplasia show s a milder phenotype but is frequently associated with severe micrognathia (Pierre- Robin sequence) . A neonate (Handa et al. Radiographics 2021) Severe metaphyseal broadening of tubular bones (“dumbbell " deformity) Delayed epiphyseal ossification of long bones , Large ossification of the talus and calcaneus Moderate platyspondyly with anterior wedging. Coronal clefts at the thoracolumbar junction Mild platyspondyly Kniest dysplasia Stickler dysplasia Broad and short ilia A neonate Mild metaphyseal broadening of tubular bones, causing mild “dumbbell " deformity Micrognathia Type II collagenopathies (2) – Stickler- Kniest family Severer

21. Type II collagenopathies : a group of allelic disorders related to abnormal type II collagen Radiological approach Radiologically, type II collagenopathies are divided into SEDC family and Stickler- Kniest family SEDC family is characterized by delayed ossification of the juxta- truncal bones. Delayed ossification of the vertebral bodies is conspicuous , especially in their posterior portion, giv ing rise to posteriorly constricted and anteriorly rounded vertebral bodies, referred to as pear- shaped vertebrae . Stickler- Kniest family is characterized by transverse overgrowth of the physis of tubular bones that gives rise to a dumbbell- like shape of the bones known as dumbbell deformity ; vertebral bodies are variably affected; epiphyseal ossification of the long bones is ret a rde d. 1 st step : Recognition of “pear- shaped vertebrae” or “dumbbell deformity” of long bones shall lead one toward the diagnosis of type II collagenopathies 2 nd step : Further subtle details can narrow down the diagnosis

22. Type XI collagenopathies (eg , OSMED) resemble Stickler- Kniest family , with similar dumbbell deformity of long bones and platyspondyly. The similarity is due to the biological close relationship between type II and XI collagens. Perlecanopathies (severe dyssegmental dysplasia to milder Schwarz- Jampel dysplasia) also resemble Stickler- Kniest family , with dumbbell deformity of long bones and anisospondyly/platyspondyly. Perlecan is a proteoglycan that is important in the basement membrane and cartilage matrix . Dyssegmental dysplasia (Perlecan) Type XI collagenopathies and p erlecanopathies – differential diagnosis for Stickler- Kniest group Short and broad thorax Dumbbell deformity of long bones Severe anisospondyly, most conspicuous in the thoracolumbar region Otospondylomegaepiphyseal dysplasia (type XI collagen) Platyspondyly with remnants of multiple coronal clefts Broad ilia Mild dumbbell deformity of long bones Defective ossification of C2 vertebra Bowing of the femur and tibia Mild platyspondyly Bowing of the femur and tibia Dumbbell deformity of long bones A young child A neonate (Handa et al. Radiographics 2021) An infant Schwarz- Jampel dysplasia (Perlecan)

23. Metatropic dysplasia family: a group of allelic disorders related to TRPV4 gene Clinical and genetic features TRPV4 mutations interfere with an interaction between cartilage synthesis and mechanical stress . TRPV4-related skeletal dysplasias comprise a continuous spectrum of disorders ranging from the severest metatropic dysplasia through the intermediate spondylometaphyseal dysplasia , Kozlowski type (SMD- K) , to the mildest autosomal dominant brachyolmia (AD- BO) . Children with metatropic dysplasia show normal length (short limbs but long trunk) as neonates , but they develop short trunk owing to progressive kyphoscoliosis; the evolution of body proportion led to the disease name metatropic (derived from Greek word metatropos = changing pattern) . Spondylometaphyseal dysplasia , Kozlowski type , and brachyolmia manifest with short stature with short trunk in early childhood .

24. Metatropic dysplasia family (TRPV4 family) Autosomal dominant brachyolmia TRPV4- related bone dysplasias (metatropic dysplasia family) show a continuous spectrum of skeletal changes, characterized by severe platyspondyly with “overfaced” pedicles (on frontal view) and “ halberd” shaped ilia . The manifestations of tubular bones are variable, ranging from severe dumbbell deformity to normal tubulation with variable degrees of metaphyseal dysplasia . Narrow thorax Severe platyspondyly Dumbbell deformity of long bones Halberd- shaped ilia Overfaced pedicles Metaphyseal dysplasia Mildly narrow thorax Overfaced pedicles Platyspondyly Halberd shaped ilia Platyspondyly and endplate irregularity Modestly overfaced pedicles Mild metaphyseal dysplasia Metatropic dysplasia (mild) Milder Milder Metatropic dysplasia (severe) Severer Narrow thorax Overfaced pedicles and severe platyspondyly “Halberd”- shaped ilia, which is an equivalent to dumbbell deformity of the long bones Dumbbell deformity of long bones A stillbirth (Handa et al. Radiographics 2021) A young infant A child Spondylometaphyseal dysplasia Kozlowski type A child

25. Metatropic dysplasia family: a group of allelic disorders related to TRPV4 gene Radiological approach 1 st step : A combination of characteristic skeletal changes allows categorization of a case as TRPV4 family Severe platyspondyly with overfaced pedicles Halberd- shaped pelvis Dumbbell deformity of the long bones, similar to that of Stickler- Kniest family , is a hallmark of metatropic dysplasia Metaphyseal dysplasia variable in manifestation 2 nd step : Further details allow differentiation Metatropic dysplasia shows all findings cited above, but metaphyseal dysplasia may have late onset SMD- K shows severe platyspondyly with overfaced pedicles and conspicuous metaphyseal dysplasia , particularly of the proximal femora, but normal modeling of long bones (absence of dumbbell deformity) AD- BO shows platyspondyly milder than that of metatropic dysplasia or SMD- K and very mild metaphyseal dysplasia Halberd- shaped ilia Overfaced pedicles – The lateral border of the vertebral bodies is locate d outside of the lateral edge of the pedicles Platyspondyly Metatropic dysplasia AD brachyolmia SMD Kozlowski

26. Diastrophic dysplasia family: a group of allelic disorders related to DTDST gene DTDST (SLC26A2) mutations cause sulfation defects of cartilage matrix proteoglycan and create a spectrum of disorders, including achondrogenesis type 1 B (ACG1B), atelosteogenesis type 2 (AO2), and diastrophic dysplasia (DTD) in decreasing order of severity . ACG1B is exclusively lethal , and AO2 is potentially lethal . DTD is the prototype of this family and shows a wide range of severities , , and it typically manifests with moderate to severe short stature with short limbs and multiple contractures of the joints . The thumbs are proximally set, hypermobile, and abducted. This distinctive physical finding is called “hitchhiker thumb . ” Spontaneous hemorrhage of the auricular cartilage occasionally occurs and causes an auricular deformity called “cauliflower ear . ” Clinical and genetic features

27. Diastrophic dysplasia family (DTDST family) Achondrogenesis type 1 B Diastrophic dysplasia DTDST- related bone dysplasias (diastrophic dysplasia family) are a spectrum of disorders characterized by impaired endochondral bone growth and maldevelopment of the joints. The common skeletal findings are cervical kyphosis , distal humeral tapering (or bifid seen from front) , elbow dislocation , and disorganized ossification of the fingers . The vertebral pedicles show wider interpedicular distance in the cervical and lumbar regions (“cobra” sign) Horizontally oriented, short ribs with splayed ends Small iliac bones with concave ends; absent ossification of the pubic and ischial bones Extremely short tubular bones with loss of longitudinal orientation The distal humeri are tapered on the lateral view The proximal fem urs are broad with prominent trochanters Cervical kyphosis Bowed radii and ulnae with elbow dislocation Long bones are short and broad Malalignment of the fingers The distal humeri are tapered on the lateral image (and bifid on the frontal image  ) Bowed radii and ulnae with elbow dislocation The distal humeri are tapered Cervical kyphosis Long bones are short and broad Malalignment of the fingers and abducted “hitchhiker thumb” Severer Ateolosteogenesis type 2 A stillbirth A neonate Severer A neonate

28. Diastrophic dysplasia family: a group of allelic disorders related to DTDST gene Radiological approach 1 st step : The skeletal abnormalities of DTD are variable, but the findings in the hand are most consistent ly seen Other findings Cervical kyphosis Distal humeral tapering or bifid appearance Elbow dislocation Severe metaphyseal cupping 2 nd step : A similar but more severe pattern suggests AO2; ACG1B is much more severe and may appear unrelated, but we can recognize the same basic pattern; the iliac bone look s like a parachute in AO2 and ACG1B Very short and oval- shaped 1 st MC Irregularly short phalanges and proximal symphalangism of the middle finger Diastrophic dysplasia ACG type 1 B AO type 2 Key images Bulbous and broad MC “hitchhiker thumb” Cervical kyphosis Diastrophic dysplasia

29. Larsen dysplasia family: a group of allelic disorders related to abnormal f ilamin B Clinical and genetic features Atelosteogenesis type 1 (AO1), atelosteogenesis type 3 (AO3), and Larsen syndrome due to FLNB mutation (Filaminopathy B) form a continuous spectrum in decreasing order of severity . Larsen syndrome is the prototype of this family and manifests with dislocation of large joints, particularly of the knee . AO3 and AO1 are more severely affected . Filaminopathies B show common facial abnormalities (hypertelorism, mid face hypoplasia, micrognathia) .

30. Larsen dysplasia family (Filaminopathies B) Atelosteogenesis (AO) type 3 Larsen dysplasia Larsen dysplasia family (filaminopathy B) is a continuous spectrum of disorders characterized by joint dislocations . Common imaging features include cervical kyphosis , distal humeral tapering , multiple dislocations , and broadening of short tubular bones . Multiple dislocations Hypoplastic fibula Distal humeral tapering Distal humeral tapering Multiple dislocations Broadening of short tubular bones Broadening of short tubular bones with deformed middle phalanges Cervical kyphosis and large odontoid process Cervical kyphosis and large odontoid process Severer A stillbirth A neonate

31. 2 nd step : Larsen dysplasia family: a group of allelic disorders related to abnormal f ilamin B Radiological approach 1 st step : The hallmarks of Larsen dysplasia family include: Multiple joint dislocation, esp. elbow, hip, and knee Broadening of tubular bones , esp. short tubular bones Distal humeral tapering and in severe cases distal femoral tapering Cervical kyphosis and broad odontoid process AO3 is a potentially lethal disorder; the skeletal changes are similar to, but more severe than, those of Larsen syndrome; broadening of short tubular bones is severe and termed a tombstone appearance AO1 is exclusively lethal; the skeletal changes are much more severe than those of AO3; long bones are broad and may be unossified; ossification of short tubular bones (other than distal phalanges ) is missing Larsen dysplasia AO1 Key images AO3 Larsen

32. Otopalatodigital syndrome family (Filaminopathy A) OPD type 1 OPD type 2 Melnick-Needles syndrome Otopalatodigital syndrome family (filaminopathy A) is a spectrum of disorders characterized by undertubulation and bowing of tubular bones and is occasionally associated with cortical irregularities. As in diastrophic dysplasia family and filaminopathy B, anomalous osseous patterning is an essential syndromic component, primarily affecting the hands and feet . Thoracic hypoplasia and wavy ribs; wide spinal canal Abnormal pattern of the undertubulated short tubular bones; delta- shaped metatarsals and phalanges; aplasia of the hallux Iliac flaring with constricted distal ilia and narrow pelvic floor Mild undermodeling of short tubular bones; short great toes; large pseudoepiphysis of the 2nd metatarsal base. A child Mild undertubulation of long bones and bowing of the tibia Bowing and undermodeling of long bones; fibular aplasia Irregular short tubular bones Thin twisted ribs; wide spinal canal Mild undermodeling of short tubular bones; short, bifid distal phalanx of the thumb; proximal ulnar projection with large pseudoepiphysis of the 2nd metacarpal; abnormal carpal bones A neonate Shortening of the hallux with malformed phalanges A child

33. Skeletal ciliopathy is a subset of ciliopathy mainly affecting the skeleton; the prototypes are Jeune asphyxiating thoracic dysplasia and Ellis – v an Creveld (EvC) syndrome; both disorders share common radiologic findings such as short ribs , short limbs , brachydactyly (later with cone- shaped epiphyses ) with or without polydactyly, trident pelvis , and premature ossification of the femoral heads . Skeletal ciliopathies Ciliopathies (a group of disorders due to abnormal ciliogenesis and intraciliary transport) with major skeletal alterations are termed skeletal ciliopathy and i nclud e Jeune syndrome, Ellis – van Creveld (EvC) syndrome, Sensenbrenner syndrome, and various types of short rib polydactyly (SRP) syndromes . C ommon skeletal changes include severe thoracic hypoplasia and severe brachydactyly with or without polydactyly; the ilia are variably affected , and the spine is not severely affected . Skeletal ciliopathies are associated with extraskeletal anomalies such as nephronophthisis, retinopathy, cardiac anomalies, etc.

34. Skeletal ciliopathies A neonate Extremely short ribs Mild shortening of long bones with bowing Short ribs Brachydactyly and post- axial polydactyly Bulbous ends of long bones (“chicken drumstick” appearance) and hypoplasia of lateral tibial plateau  Trident - shaped ilia A neonate Shortening of long bones Trident - shaped ilia Cone- shaped epiphyses A 3- year- old Cone- shaped epiphyses and postaxial polydactyly A 4- year- old Jeune asphyxiating thoracic dysplasia Ellis – v an Creveld syndrome Postaxial polydactyly

35. Radiological approach 1 st step : T he skeletal changes Skeletal ciliopathies: a heterogeneous group of skeletal disorders with abnormal primary cilia that lead to the diagnosis of skeletal ciliopathies are : Extremely short ribs Short digits with or without polydactyly Cone- shaped epiphysis of short tubular bones manifest ing in early childhood Premature ossification of the femoral and humeral heads Normal spine or mild modification of vertebral bodies Trident pelvis in Jeune, EvC, and and most types of SRPs 2 nd step : Further details can narrow down the diagnosis Key images Jeune asphyxiating thoracic dysplasia Trident shaped ilia Postaxial polydactyly bulbous appearance of long bones Ellis- van Creveld syndrome bulbous appearance of long bones Normal pelvis Sensenbrenner syndrome

36. Chondrodysplasia punctata (CDP) is a heterogeneous group of disorders characterized by abnormal punctate calcifications ( puncta , stippling) in the cartilage, particularly the epiphyseal cartilage; puncta disappear by age 2– 4 years and evolve into epiphyseal dysplasia. Subtypes of CDP are distinguishable from each other on the basis of the distribution of the puncta and other disease- specific skeletal alterations. Punctata family

37. Punctata family: a heterogeneous group of disorders with characteristic stippling Radiological approach 1 st step : Identification of puncta is the first step. Puncta are only seen until the age of 2 – 4 years , so early radiographs are very helpful 2 nd step : Distribution of the puncta allows differentiation; disease- specific bone changes are : CDP- CH: a symmetric stippling with asymmetric limbs and severe spondylar deformity R- CDP: stippling esp ecially prominent in the patella and very mild puncta of the spine with rhizomelic shortening of the limbs and multiple coronal clefts CDP- BT: s tippling prominent in the tarsal bones , sacrococcyx, and cervical spine with brachytelephalangy and defective ossification of the cervical spine The etiology of CDP is heterogeneous . CDP Conradi- Hunermann type (CDP- CH) is caused by mutations in EBP leading to abnormal cholesterol biosynthesis . CDP r hizomelic type ( R- CDP) is caused by mutations in PEX7 leading to abnormal peroxisome biosynthesis . CDP brachytelephalangic type ( CDP- BT) is typically caused by ARSE mutations leading to impairment of the v itamin K activation cycle . Puncta may also occur in acquired disorders such as warfarin embryopathy and maternal collagen vascular diseases (eg , systemic lupus erythematosus) that commonly masquerade as CDP- BT . Regardless of the etiology, affected children share severe nasal hypoplasia; the nasal malformation is particularly conspicuous in CDP- BT, which is termed Binder facial phenotype . R- CDP CDP- CH CDP- BT CDP- CH Clinical and genetic features

38. Punctata family CDP Conradi- Hunermann type CDP Rhizomelic type CDP brachytelephalangic type Chondrodysplasia punctata (CDP) is a heterogeneous group of disorders characterized by abnormal punctate calcifications (puncta, stippling) in the cartilage, particularly the epiphyseal cartilage; puncta disappear by age 2 – 4 years and evolve into epiphyseal dysplasia. Subtypes of CDP are distinguishable from each other on the basis of the distribution of the puncta and other disease- specific skeletal alterations . Spinal puncta and spinal hypoplasia are seen in the lower lumbar spine Short humeri with metaphyseal flaring The distal phalanges of the hand are short with broad terminal tufts and a narrow phalangeal base (with puncta  ) Prominent patellar puncta The ilia are hypoplastic with short greater sciatic notches and horizontal acetabula Short fem urs Multiple puncta A neonate A neonate An infant Multiple puncta in the tarsal bones Multilevel coronal clefts Multiple puncta predominantly on the right side. Long bones are asymmetrically short, more severe on the right Multiple puncta in the laryngeal cartilage, sternum, cervical spine

39. Osteogenesis imperfecta group: a group of disorders related to type I collagen Most cases (over 95%) are autosomal dominant and caused by heterozygous mutations in type I collagen genes ( COL1A1 or COL1A2 ) leading to abnormal intramembranous bone formation. Many other genes have been reported and m ainly manifest as severe OI . Severe form manifests as in utero multiple fracture s leading to striking accordion- like deformity of the limbs . Mild form manifests with recurrent fractures without overt trauma, which have prenatal or postnatal onset . Type 5, due to IFITM5 gene , is distinctive . Extraskeletal manifestations include joint laxity, tissue fragility, dentinogenesis imperfecta, hearing impairment, and blue sclerae (hallmark of OI type 1 ) . Clinical and genetic features

40. Osteogenesis imperfecta group OI (severe, type 3 ) OI (mild, type 1 ) Osteogenesis imperfecta (OI) is a family of disorders characterized by variable degrees of osteoporosis and repeated fractures . Mild OI manifests with multiple w ormian bones and slender bones with fractures and/or bowing. Severe OI manifests as severely defective skull ossification and crumpled- appearing thick bones as a result of in utero fractures/healing. These manifestations look different at first glance, but they share the same process with difference s in severity only . Sillence classification has been used for clinical classification . Thick and deformed “accordion- like” long bones due to in utero fractures/healing Multiple rib fractures and vertebral body compression fractures Long bones are mildly slender and bowed with an old fracture in the left distal tibia. Generalized osteoporosis Multiple w ormian bones along the lambdoid sutures Sillence classification Type 1 : b lue (transparent) sclera, mild Type 2 : p erinatally lethal Type 3 : s everely deformed, wheelchair bound Type 4 : w hite sclera, mild to moderate Type 5 : h yperplastic callus causing ossification of the intraosseous membrane A neonate Severer A child

41. Osteogenesis imperfecta group: a group of disorders related to type I collagen Radiological approach 1 st step : Slim and fragile bones with repeated fractures. I ntrauterine fractures lead to thick, crumpled bone. Impaired calvarial intramembranous ossification cause s multiple w ormian bones 2 nd step : The onset and severity determine the subtype Some types of OI are radiologically distinguishable OI type 5 : hyperplastic callus and ossification of the interosseous membrane OI type 3 : may show ”popcorn” calcification in epi metaphysis of the knee as a result of microtraumas OI type 2C (type I collagen C- propeptide mutations): lethal variant with slender twisted long bones and metaphyseal sclerosis Dense- bone OI ( BMP gene or type I collagen cleavage site mutation) : coarse sclerotic trabeculae with short ulna and bowed long bones OI type 3 OI type 2C Multiple w ormian bones and osteoporosis with slim bones and prenatal bowing OI type 1 / 4 OI type 5 IFITM5 mutations Hyperplastic callus Ossification of the interosseous membrane

42. Osteopetrosis group: a group of disorders with dense but brittle bones Clinical and genetic features Most types are caused by defective absorption of immature bones as a result of osteoclast dysfunction or osteoclastogenesis. Abundant immature bones cause dense but brittle bones . Many genes that are related to OP have been reported . Infantile form ( autosomal recessive ) is most commonly associated with mutations in TCIRG1 and manifests with failure to thrive, bone marrow failure with recurrent infection and hepatosplenomegaly, and compressive neurologic abnormalities (cranial nerve palsy) . Late- onset form ( autosomal dominant ) is most commonly caused by CLCN7 mutations and manifests in late childhood to adolescence , with susceptibility to fractures and dental caries .

43. Osteopetrosis group Osteopetrosis (OP) is a heterogeneous group of conditions characterized by generalized bone sclerosis . O P comprises three clinical groups (infantile, intermediate, and late onset ), which are based on the timing of onset. Pyknodysostosis is a special form of OP. Undermineralized osteoids manifest as osteopetrorickets and periosteal cloaking Bones are generally sclerotic with poor corticomedullary differentiation Generalized sclerosis Sandwich appearance of the vertebral bodies with fracture Old fractures of the tibiae Acro - osteolysis (pathognomonic) A neonate O P (early onset) O P (late onset) Pyknodysostosis Sclerotic craniofacial bones, particularly the skull base A young adult patient with trauma Widely opened fontanels Severe micrognathia with an obtuse mandibular angle Generalized sclerosis with preserved corticomedullary differentiation An adult patient with trauma Severer

44. Osteopetrosis group: a group of disorders with dense but brittle bones Radiological approach 1 st step : The common radiologic pattern is generalized osteosclerosis with poor corticomedullary differentiation Osteosclerosis may be conspicuous at the bone end, related to sandwich appearance of vertebral bodies Defective bone absorption can wax and wane, leading to alternating dense and lucent bands of long bones and a bone- in-bone appearance 2 nd step : Infantile form may also be accompanied by metaphyseal rachitic changes (osteopetrorickets) Infantile form is associated with modeling failure, leading to Erlenmeyer- flask deformity A variant of OI is associated with platyspondyly and termed dysosteosclerosis Pyknodysostosis is a special form, characterized by sclerosis, defective calvarial ossification, and acro - osteolysis Corticomedullary differentiation is preserved Dysosteosclerosis Pyknodysostosis Osteopetro- rickets (infantile OP) O steopetrosis Erlenmeyer- flask (infantile OP) Bone- in- bone Sandwich appearance of vertebral bodies

45. Focal sclerotic bone dysplasias The family of focal sclerotic bone dysplasias comprises a het e rogeneous group of disorders that manifest with focal bone sclerosis. This family includes osteopoikilosis , osteopathia striat , and melorrheostosis

46. Reeder ’s and Felson's Gamuts in Radiology Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development (4th Edition) Hall’s Fetal and Perinatal Skeletal Dysplasias Taybi ’s and Lachman’s Radiology of Syndromes, Metabolic Disorders and Skeletal Dysplasias Smith’s Recognizable Patterns of Human Malformation OMIM Pubmed Further reading