ASNR 54th Annual Meeting, Washington, DC, May 23-26 eEdE -194 Neuroimaging findings in pediatric genetic skeletal disorders: a pattern-recognition approach Matthias W. Wagner, Andrea Poretti, Thangamadhan Bosemani, Jane E. Benson, Thierry A.G.M. Huisman Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, MD ASNR 54th Annual Meeting, Washington, DC, May 23-26

Disclosure We have nothing to disclose No relevant financial relations interfering with our presentation

Outline Definition of genetic skeletal disorders (GSD) Diagnosis + challenges of GSD Spectrum of central nervous system (CNS) abnormalities in GSD + pattern-recognition approach The skeleton can predict possible CNS findings Application of the pattern-recognition approach illustrated by 5 cases Take home messages

What are GSD? Heterogeneous group of disorders with intrinsic abnormality in growth + remodeling of cartilage + bone Features of GSD: Malformation Disproportionate growth Deformation Individually rare, but overall incidence = 1:5000 Superti-Furga A et al, Am J Med Genet, 2001; Alanay Y et al, J Clin Res Pediatr Endocrinol, 2011

Warman ML et al, Am J Med Genet A, 2011 What are GSD? Nosology and Classification of Genetic Skeletal Disorders (2010) = 456 disorders classified by: Clinical features Imaging findings Genetic/molecular criteria >200 GSD are systemic disorders with involvement of various organs including CNS, in addition to the skeleton Warman ML et al, Am J Med Genet A, 2011

How are GSD diagnosed? Comprehensive clinical history Analysis of longitudinal growth patterns Clinical evaluation of the child + family Complete radiographic survey Savarirayan R and Rimoin DL, Best Pract Res Clin Endocrinol Metab, 2002

Skeletal and systemic involvement in GSD Skeletal involvement Systemic involvement Head + neck: dental malocclusion, cleft palate Limbs: short stature, ulnar/ radial hypoplasia Hands + feet: carpal fusion, polydactyly, ectrodactyly Thorax: pectus excavatum, rib anomalies Spine: platyspondyly, spina bifida, vertebral fusion Pelvis: congenital hip dislocation Heart: congenital heart defects Lungs: pulmonary hypoplasia Genitals: hypospadias, cryptorchidism Gastro-intestinal: pyloric stenosis, omphalocele Blood: eosinophilia, anemia, hypoplastic megakaryocytes Eyes: myopia, retinal detachment

CNS involvement in GSD Documented in > 200 GSD Pathomechanism: Caused by the underlying genetic defect Secondary to the bone abnormality Important role for long-term prognosis of children with GSD = should not be missed Detailed familiarity with GSD-linked CNS findings may guide diagnostic/neuroimaging approach and vice versa non-neuroimaging strategy

Pattern-recognition approach Detection of skeletal pathology (e.g. X-ray) Based on skeletal involvement: Size/number: skull, torso, limbs, or acra Dynamic/structural changes: mineralization, ossification, or bone age Shape: skull, torso, joints, limbs, or acra Involvement of metaphysis or epiphysis  Differential diagnosis list of possible GSD For each GSD  List of CNS abnormalities

Pattern-recognition approach

Case 1: skeletal phenotype Preaxial polydactyly Mesoaxial polydactyly Postaxial polydactyly Poretti A et al, Orphanet J Rare Dis, 2012

Case 1: differential diagnosis Postaxial polydactyly Bardet-Biedl syndrome Carpenter syndrome Greig cephalosyndactyly Hydrolethalus syndrome Jeune disease Laurin-Sandrow syndrome Meckel syndrome Oral-facial digital syndrome 1 Oral-facial digital syndrome 4 Oral-facial digital syndrome 6 Pallister-Hall syndrome Rubinstein-Taybi syndrome Smith-Lemli-Opitz syndrome Majewski syndrome Trisomy 13 Preaxial polydactyly Carpenter syndrome Craniofrontonasal syndrome Greig cephalosyndactyly Laurin-Sandrow syndrome Majewski syndrome Oral-facial digital syndrome 1 Oral-facial digital syndrome 4 Oral-facial digital syndrome 6 Townes-Brocks syndrome Trisomy 21

 Oral facial digital syndrome type 6 Case 1: CNS phenotype Hypoplasia + dysplasia of the vermis (long arrow), enlarged posterior fossa, abnormal morphology of the brainstem, hypothalamic hamartoma (short arrow), callosal dysgenesis Molar tooth sign (long arrows), cerebellar hypoplasia + dysplasia, hypothalamic hamartoma (short arrow)  Oral facial digital syndrome type 6 Poretti A et al, AJNR, 2008

Oral facial digital syndrome type 6 Skeletal phenotype CNS phenotype Skull: hypertelorism, macrognathia, cleft palate Acra: polydactyly (pre-, meso-, or postaxial) Molar tooth sign = elongated, thickened + horizontally oriented superior cerebellar peduncles + deepened interpeduncular fossa Cerebellar vermian hypoplasia + dysplasia Hypothalamic hamartoma Additional findings possible (dysplastic brainstem, callosal dysgenesis, …) Poretti A et al, Orphanet J Rare Dis, 2012

Case 2: skeletal phenotype Rhizomelic shortening of limbs Anterior beaked vertebral bodies Macrocephaly

Case 2: differential diagnosis Macrocephaly Achondroplasia Acrocallosal syndrome Campomelic dysplasia Cleidocranial dysplasia Cowden syndrome Craniodiaphyseal dysplasia Craniometaphyseal dysplasia Diaphyseal dysplasia, Camurati-Engelmann Fragile X-syndrome GM1 Gangliosidosis Greig cephalosyndactyly Hydrolethalus syndrome Hypochondroplasia Hypomelanosis of Ito Klippel-Trenauny syndrome Lenz-Majewski syndrome Marfan syndrome Marshall-Smith syndrome Mucopolysaccharidosis Mucolipidosis 2 Noonan syndrome Osteogenesis imperfecta Etc. Rhizomelic limb shortening Achondroplasia Chondrodysplasia punctata 1 Opsismodysplasia Pseudo-achondroplasia Spondylo-enchondrodysplasia Spondylo-epi-metaphyseal dysplasia Spondylo-metaphyseal dysplasia Anterior beaked vertebral bodies Achondroplasia Fucosidosis GM1 Gangliosidosis Mucopolysaccharidosis Mucolipidosis 2 Pseudo-achondroplasia Spondylo-epi-metaphyseal dysplasia

Case 2: CNS phenotype  Achondroplasia Cervicomedullary compression Foramen magnum stenosis  Achondroplasia Bosemani T et al, Dev Med Child Neurol, 2014

Achondroplasia Skeletal phenotype CNS phenotype Skull: frontal bossing, depressed nasal bridge, macrocephaly Torso: narrow chest, anterior beaked vertebral body, thoracolumbar kyphosis Limbs: rhizomelic limb shortening Acra: brachydactyly Other: interpedicular distances of lumbar spine ↓, translucency of proximal femur ↑ Cervicomedullary compression in 35% of patients Ventriculomegaly Spinal nerve compression

Case 3: skeletal phenotype Fragility of bones, pathologic fractures, bowed tubular bones Platybasia (skull base angle > 143 degrees) +/- basilar invagination

Case 3: differential diagnosis Fragility of bones / pathologic fractures Antley-Bixler syndrome Cutis laxa Dysosteosclerosis GM1 Gangliosidosis Hypophosphatasia Maffucci syndrome McCune-Albright syndrome Mucolipidosis 2 Osteogenesis imperfecta Etc. Basilar invagination Achondroplasia Cleidocranial dysplasia Crouzon syndrome Hajdu-Cheney syndrome Hypophosphatasia Klippel-Feil syndrome Mucopolysaccharidosis Osteopetrosis Pyknodysostosis Bowed tubular bones Achondroplasia Antley-Bixler syndrome Campomelic dysplasia Chondrodysplasia punctata X1 Cornelia de Lange syndrome Diastrophic dysplasia Dyssegmental dysplasia Epidermal nevus syndrome GM1 Gangliosidosis Hydrolethalus syndrome Hypophosphatasia Klippel-Trenauny syndrome Larsen syndrome Maffucci syndrome Mesomelic dysplasia Mucopolysaccharidosis Mucolipidosis 2 Neurofibromatosis 1 Oto-palato-digital syndrome 2 Melnick-Needles syndrome Majewski syndrome Thanatophoric dysplasia

 Osteogenesis imperfecta Case 3: CNS phenotype Ventriculomegaly Platybasia  Osteogenesis imperfecta

Osteogenesis imperfecta Skeletal phenotype CNS phenotype Osteopenia Fragility of bones Short stature Bowed tubular bones Scoliosis, kyphosis Platybasia (skull base angle > 143 degrees) ± secondary basilar invagination Cervicomedullary compression Ventriculomegaly Syringohydromyelia Cerebellar hypoplasia (particularly in WNT1 mutations)

Case 4: skeletal phenotype Brachydactyly, bullet-shaped phalanges Platyspondyly, gibbus deformity Broad clavicles

Case 4: differential diagnosis Platyspondyly: Achondroplasia Diastrophic dysplasia Dysosteosclerosis Ehlers-Danlos syndrome Fucosidosis Hypophosphatasia Larsen syndrome Maffucci syndrome Metatropic dysplasia Mucopolysaccharidosis Osteogenesis imperfecta Ollier disease Opsismodysplasia Pseudoachondroplasia Rothmund-Thomson syndrome Schwartz-Jampel syndrome Spondyloepiphyseal dysplasia congenita Sotos syndrome Etc. Brachydactyly: Achondroplasia Acrocallosal syndrome Acrodysostosis Acromesomelic dysplasia Bohring Opitz syndrome Carpenter syndrome Diastrophic dysplasia Hypochondroplasia Mucopolysaccharidosis Etc. Thickened clavicles: Craniodiaphyseal dysplasia Craniometaphyseal dysplasia Diastrophic dysplasia Dysosteosclerosis Fucosidosis Lenz-Majewski syndrome Mucolipidosis 2 Mucopolysaccharidosis Etc.

Alqahtani E et al, Eur J Paediatr Neurol, 2014 Case 4: CNS phenotype Diffuse T2↑ signal of the supratentorial white matter (short arrow), enlarged perivascular spaces (long arrow), ventriculomegaly Macrocephaly, cerebellar hypoplasia, enlargement of the sella (short arrow), thickening of the diploe (long arrow)  Mucopolysaccharidosis Alqahtani E et al, Eur J Paediatr Neurol, 2014

Mucopolysaccharidosis Skeletal phenotype = Dysostosis multiplex CNS phenotype Skull: Macrocephaly, frontal bossing Torso: Platyspondyly and kyphotic deformity, thickened clavicles Limbs: Shortened long bones, dysplasia of the acetabuli, genu valgum Acra: Brachydactyly (bullet- shaped phalanges) Epiphyses: hypoplastic, irregular White matter abnormality (type 1, 2, 3, 7) Enlarged perivascular spaces (type 1, 2, 3, 6) Ventriculomegaly (type 1, 2, 3) Cerebral atrophy (type 1, 2, 3) Spinal stenosis (type 1, 4, 6) Rare: Macrocerebellum + enlarged cerebellar perivascular spaces (type 1, 2)

Case 5: skeletal phenotype Short 1st metacarpal, 5th finger clinodactyly Oligodactyly Absent ulna

Case 5: differential diagnosis Reduction defects: Adams-Oliver syndrome Al Awadi/Raas-Rothschild syndrome CHILD syndrome De Lange syndrome Ectrodactyly-ectodermal dysplasia Lethal multiple pterygium syndrome Möbius syndrome Etc. Adactyly, monodactyly, oligodactyly: Baller-Gerold syndrome Bohring-Opitz syndrome CHILD syndrome De Lange syndrome DOOR syndrome Ectrodactyly-ectodermal dysplasia Möbius syndrome Oral facial digital syndrome type 4 Melnick-Needles disease Etc. Clinodactyly: Bardet-Biedl syndrome Carpenter syndrome Cerebrocostomandibular syndrome Cohen syndrome Craniofrontonasal syndrome De Lange syndrome DOOR syndrome Ectrodactyly-ectodermal dysplasia Ehlers-Danlos syndrome Filippi syndrome Hypomelanosis of Ito Lethal multiple pterygium syndrome Marden-Walker syndrome Meckel syndrome Miller-Dieker syndrome Taybi-Linder cephaloskeletal syndrome Etc.

Case 5: CNS phenotype  Cornelia de Lange syndrome Atrophy of the frontal lobes, ventriculomegaly  Cornelia de Lange syndrome

Cornelia de Lange syndrome Skeletal phenotype CNS phenotype Spectrum of reduction defects: absent forearms, oligodactyly, short first metacarpal Fifth finger clinodactyly Abnormal elbow extension Proximally placed thumb Partial second and third syndactyly toes Frontal lobe atrophy Ventriculomegaly Inferior vermis hypoplasia

Take home message GSDs = large number of heterogeneous + individually rare diseases, but overall incidence is high Many GSDs = systemic disorders with CNS involvement CNS involvement = important for prognosis Pattern-recognition approach helpful for diagnosis + evaluation of CNS involvement Brain can predict skeleton; skeleton can predict the brain