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Journal of Back and Musculoskeletal Rehabilitation 00 (2014) 1–16 DOI 10.3233/BMR-140558 IOS Press

Genetic skeletal dysplasias: A guide to diagnosis and management Mathew David Sewell∗ , Amanjot Chahal, Nawfal Al-Hadithy, Gordon W. Blunn, Sean Molloy and Aresh Hashemi-Nejad

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Department of Paediatrics, The Royal National Orthopaedic Hospital, Stanmore, Middlesex, UK

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Abstract. The skeletal dysplasias are a large, heterogeneous group of genetic disorders characterised by abnormal growth, development and remodelling of the bones and cartilage that comprise the human skeleton. They typically present with disproportionate short stature in childhood, or premature osteoarthritis in adulthood. The latest classification lists 456 disorders under 40 group headings differentiated by specific clinical, radiographic and molecular criteria. Establishing an accurate diagnosis is important to predict final height, expected complications and treatment, and for specific genetic and psychological counselling. In addition to the skeletal disorder, individuals frequently demonstrate abnormalities of hearing, vision, neurological, pulmonary, renal or cardiac function that require multidisciplinary assessment. This review provides a guide to diagnosis and discusses management principles for the common limb and spinal abnormalities that affect quality of life for the majority.

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QoL, GH,

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osteogenesis imperfecta; fibroblast growth factor receptor 3; growth hormone; matrilin-3 protein; cartilage oligomeric matrix protein; multiple epiphyseal dysplasia; diastrophic dysplasia sulphate transporter; quality of life; growth hormone

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OI, FGFR3, GH, MATN3, COMP, MED, DTDST,

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Abbreviations

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Keywords: Skeletal dysplasia, chondrodysplasias, management, genetics, diagnosis, spine

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1. Introduction

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Skeletal dysplasias (SD) are a large, heterogeneous group of genetic disorders characterised by abnormal

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∗ Corresponding

author: Mathew Sewell, Department of Paediatrics, The Royal National Orthopaedic Hospital, Brockley Hill, Stanmore, Middlesex HA7 4LP, UK. E-mail: matbuzz1@hotmail. com.

growth, development and maintenance of skeletal cartilage and bone. They have generalised effects on the skeleton, which differentiates them from dysostoses, which are malformations of individual bones or group of bones that form a sub-group within the SDs [1]. SDs typically present with short stature in childhood, however due to their heterogeneity, musculoskeletal effects range in severity from premature arthritis in average height individuals to severe short stature with death in the perinatal period. They frequently arise from new dominant mutations, although all types of inheritance may be described (autosomal, X-linked, dominant and recessive) [2,3], including chromosomal abnormalities [4,5]. Although individual dysplasias are rare, collectively birth incidence is 1 in 5000, which represents 5% of children born with birth defects [6]. True incidence is likely to be higher due to under-diagnosis [7,8]. The spine and limbs are frequently affected, and in addition to musculoskeletal abnormalities, children may demonstrate abnormalities in hearing, vision, neurological, respiratory, cardiac, or renal function and have psychological problems [9–15].

c 2014 – IOS Press and the authors. All rights reserved ISSN 1053-8127/14/$27.50 

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3. Diagnosis of skeletal dysplasia

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3.1. History and presenting features

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The commonest presenting feature for a child with SD is disproportionate short statute (asymmetric decrease in trunk or limb length). Disproportionate short stature is sub-divided into short-trunk or short-limb variety. In short-limb dwarfism, rhizomelia refers to proximal segment shortening (humerus/femur), mesomelia, middle segment (forearm/tibia) and acromelia, distal segment (hand/foot). Micromelia refers to an abnormally short limb(s), and brachydactyly, short digits. Individuals with proportionate short stature (symmetrical decrease in trunk and limb length) are more likely to have a systemic cause for growth failure (renal, cardiac, endocrine or nutritional) or present as part of a syndrome caused by other genetic aberrations. Occasionally a child may present with motor delay or as an apparent ‘normal variant’ with bow-legs, knock-knees, in-toeing gait or flatfeet [7]. The history should ascertain when the short stature was first recognised: prenatally or later during child-

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3.2. Examination

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Sitting and standing heights, upper/lower segment (U/L) ratio, arm span and head circumference should be recorded sequentially on growth charts. Lower segment (floor to symphysis pubis) represents leg length. Upper segment (total height minus lower segment) and sitting heights represent head and trunk length. Upper/ lower segment and arm span/sitting height ratios determine proportions (spine or limb shortening). Patterns emerge when anthropometric measurements are plotted on growth charts; the rhizomelic short-limb dwarfism achondroplasia demonstrates a greater than normal head circumference, increased U/L segment ra-

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Pre-1970’s, most individuals with short stature were diagnosed as having pituitary dwarfism (proportionate dwarfism), achondroplasia (short-limb dwarfism), or Morquio’s (short-trunked dwarfism) [2]. With increasing awareness of the clinical and genetic heterogeneity, there was need to develop a uniform classification, the ‘International Nomenclatures of Constitutional Diseases of Bone,’ which was initially formulated in 1970 and has been revised several times [1, 16,17]. The most recent classification combines clinical (e.g. short-limb dwarfism) and radiographic (e.g. epiphyseal dysplasia) descriptions with one that recognises groups of ‘dysplasia families’ that share a common molecular abnormality (e.g. type II collagen disorders). The 2010 revision lists 456 disorders under 40 group headings [17]. Groups are differentiated by specific molecular, biochemical, and/or radiographic criteria (Table 1). Of these conditions, 316 are associated with mutations in one or more of 226 different genes [17]. Classification is continually evolving and it is not always possible to classify patients into a defined group. Diagnosis is based upon clinical and radiological examination, supplemented when possible, with histologic analysis of growth plate tissue [18] (Table 2).

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hood. Most SDs become apparent in later childhood; in pseudoachondroplasia, birth lengths are normal, with short-limb dwarfism presenting around 3 years [19]. Around 100 dysplasias are recognisable at birth, including the commonest, achondroplasia [2,20,21], which is a short-limb dwarfism caused by failure of endochondral ossification in the proliferative zone of the physis due to a fibroblast growth factor receptor 3 (FGFR3) mutation [22]. Antenatal history is important, as these disorders may be detectable prenatally on 20-week ultrasound [23,24]. Any fetus with femora or humeri length measurements < 5th centile, or < −2SD below the mean in the second trimester (< 24 weeks) should be evaluated in a specialist centre [24]. One of the most important things to ascertain is risk of infantile lethality, commonly from small chest circumference causing pulmonary insufficiency, or concomitant visceral abnormalities [24,25] (Table 3). Based on ultrasound criteria, chest-to-abdominal circumference ratio of < 0.6 [26], and femur length-to-abdominal circumference ratio < 0.16 are strongly suggestive of lethality [27]. Prenatal diagnosis is also possible by molecular analysis of DNA derived from chorionic villus cells or amniocentesis, however this is a complex issue and requires discussion with a geneticist [24]. The family history should include parental height, other family members affected and parental consanguinity. Some SDs present specific symptoms such as susceptibility to infection and abnormal hair in cartilage-hair hypoplasia (McKusick metaphyseal dysplasia) [13], congenital heart malformation and multiple joint dislocations in Larsen’s syndrome [12], and heart defects, polydactyly and nail deformity in chondroectodermal dysplasia (Ellis-van Creveld syndrome) [10, 14].

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2. Classification

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Table 1 International nosology and classification of genetic skeletal disorders: 2010 revision with 40 defined groups differentiated by molecular, biochemical and/or radiographic data [17]. The complete nosology lists 456 disorders. This table lists all 40 groups, and has been modified to include descriptions of only the more common skeletal disorders within each group with underlying gene/protein abnormality and genetics Genetic group/name of skeletal disorder 1. FGFR3 group Achondroplasia

Gene defect/ Inheritance Distinguishing features abnormal protein AD

Type of rhizomelic short-limb dwarfism with macrocephaly, frontal bossing, maxillary hypoplasia, button-nose, ‘trident’ hands, thoraco-lumbar kyphosis, exaggerated lumbar lordosis, genu varum and coxa valga. Mean final height is 130 cm for men and 125 cm for females. Foramen magnum stenosis is a problem in infants that may manifest as central or obstructive sleep apnoea, excessive sweating, hypotonia and delayed motor milestones. In adults spinal stenosis needs prompt recognition and treatment to prevent paraplegia. Lifespan and intelligence are normal. Radiographs show short long bones with metaphyseal flaring and a ‘V-shaped’ distal femoral epiphysis. Lateral spine radiographs show scalloping of the vertebral bodies posteriorly, and anterior wedging at the thoracolumbar junction. The key feature is narrowing of the interpediculate distance from L1-L5.

COL2A1/Type 2 AD collagen

Epiphyseal fragmentation with spine involvement. Short trunk dwarfism typically presents around the age of 2–3 years. Classic features include progressive coxa vara, tibia vara with internal tibial torsion, platyspondyly, thoracic kyphoscoliosis with excessive lumbar lordosis, odontoid hypoplasia, atlanto-axial instability and possible myelopathy. Ophthalmic review is mandatory to exclude retinal pathology.

COL2A1/Type 2 AD collagen

Short trunk dwarfism with kyphoscoliosis, retinal detachment, dumbbellshaped femora and hypoplastic pelvis and spine.

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Kniest syndrome 3. Type 11 collagen group

Fibrillar collagen found in extracellular matrix.

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7. Filamin group and related disorders

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5. Perlecan group

AR

Larsen syndrome (dominant)

Short limb ‘twisted’ dwarf with cleft pallet, cauliflower ears, thoracolumbar kyphoscoliosis, genu valgum, rigid club feet, ‘hitch-hiker’s thumb’ (abducted and proximally displaced thumb due to short 1st metacarpal), cervical kyphosis and C1/2 instability

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DTDST/ SLC26A2 sulphate transporter

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4. Sulphation disorders group Diastrophic dysplasia

6. Aggrecan group

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2. Type 2 collagen group Spondyloepiphyseal dysplasia congenital (SEDC)

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FGFR3/FGFR3

FLNB/Filamin B AD

8. TRPV4 group

Heparan sulphate proteoglycan, which is a structural component of the basement membranes, and may be involved in stabilisation of other molecules, and cell-to-cell adhesion.

Most abundant proteoglycan in extracellular matrix

Multiple joint dislocations (especially congenital knee dislocations), flattened facies, scoliosis, clubfeet, cervical kyphosis TRPV4 is a calcium-permeable ion channel of the vanilloid subfamily of TRP channels

9. Short-rib dysplasia (SRP) (with or without polydactyly) group 10. Multiple epiphyseal dysplasias and pseudachondroplasia group Pseudoachondroplasia

COMP/COMP

AD

Characterised by short limb dwarfism and ligamentous laxity which becomes clinically apparent after 3 years. Clinically similar to achondroplasia but children have normal facies. Platyspondyly is evident from birth. Other features include cervical instability, scoliosis with increased lumbar lordosis, hip, knee and elbow flexion contractures, lower limb bowing and flexible flat feet. Radiographs show cupped, flared metaphyses with small fragmented epiphyses.

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M.D. Sewell et al. / Genetic skeletal dysplasias: A guide to diagnosis and management Table 1, continued

Genetic group/name of skeletal disorder Multiple epiphyseal dysplasia Type 1 Types 2,3,6

Gene defect/ Inheritance Distinguishing features abnormal protein AD COMP/COMP COL9A3/type 9 AD collagen MATN3/Matrilin AD 3

Short limbed dwarfism with epiphyseal fragmentation at multiple epiphyses. Bilateral hip involvement is most common and tends to result in early-onset arthritis. Short, stunted metacarpals/metatarsals and valgus knees are seen. Epiphyseal changes are symmetrical and most apparent in the lower limbs. Vertebrae are normal. Clinical and radiographic features are absent at birth.

11. Metaphyseal dysplasias Metaphyseal chondrodysplasia Schmid type

COL10A1/type 10 collagen

AD

Long bone metaphyseal changes with normal epiphyses Short-limbed dwarfism usually diagnosed when the child is 2–3 years old. Features include coxa vara (causing a waddling gait), genu varum and excessive lumbar lordosis

Metaphyseal chondrodysplasia McKusick type (cartilage-hair hypoplasia)

RMRP/RNA component of RNAse H

AR

Short limbed dwarfism that becomes clinically apparent after 2–3 years. Children have bowed legs, ligamentous laxity, short, broad feet and hands and odontoid hypoplasia with atlantoaxial instability. The hair is fine (small diameter) and usually light. There is an increased risk of malignancy and immunological compromise associated with this dysplasia.

Metaphyseal chondrodysplasia Jansen type

PTHR1/PTH or AD PTHrP receptor 1

Short-limbed dwarf with wide eyes, hypercalcaemia and striking bulbous metaphyseal expansion of long bones. Severe limb shortening, prominent forehead and micrognathia make the diagnosis possible at birth. Flexion contractures in the hips and knees develop with age, causing walking difficulties.

SEDL/Sedlin

Similar to SEDC (in group 2) but clinically less severe and manifests at older age (8–10 years). Primarily affects spine and large joints with premature osteoarthritis and scoliosis. No lower limb angular deformities.

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Type 5

14. Severe spondylodysplastic dysplasias

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15. Acromelic dysplasias

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16. Acromesomelic dysplasias

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PseudoSHOX/short stature homeobox AD gene

Short stature with short forearms and legs and a bayonet-like deformity of the forearms (Madelung’s deformity)

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17. Mesomelic and rhizomesomelic dysplasias Dyschondrosteosis (Leri-Weill)

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13. Spondylo-epi(-meta) physeal dysplasias (SE(M)D) Spondyloepiphyseal dysplasia tarda, X-linked (SED-XL)

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12. Spondylometaphyseal dysplasias (SMD)

18. Bent bones dysplasias

19. Slender bone dysplasia group

20. Dysplasias with multiple joint dislocations 21. Chondrodysplasia punctata (CDP) group 22. Neonatal osteosclerotic dysplasias 23. Increased bone density group (without modification of bone shape) Osteopetrosis, severe neonatal or multiple infantile forms

AR

Severe form. ‘Marble’ bone or ‘bone within a bone’ appearance on radiographs. Lack of cranial remodelling may result in blindness and cranial nerve palsies. Lack of medullary bone results in hepatosplenomegaly, aplastic anaemia and recurrent infection. Bone marrow transplant can be life saving during childhood.

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Table 1, continued Genetic group/name of skeletal disorder Osteopetrosis, late onset form

Gene defect/ Inheritance Distinguishing features abnormal protein multiple AD Mild form. Generalised osteosclerosis including characteristic ‘rugger jersey’ spine on radiographs. Often diagnosed incidentally.

AD

Associated muscle weakness frequently causes late walking in children. Radiographs demonstrate symmetrical cortical thickening of long bones with widened diaphysis and sclerosis from increased bone formation.

25. Osteogenesis imperfecta and decreased bone density group Osteogenesis imperfecta, non de- COL1A1 and forming form (OI type 1) COL1A2/type 2 collagen

AD

Commonest form. Multiple fractures occur in childhood. Fractures typically start when the child learns to walk. Fractures reduce in frequency after puberty, but then there is increase later in life due to disuse osteoporosis. Children demonstrate mild short stature and there is mild skeletal deformity, as fractures heal but bone does not remodel well. Blue sclerae are present in childhood, sensorineural or mixed hearing loss develops in early adult life. Teeth may manifest dentinogenesis imperfecta (DI) due to abnormal dentin.

AD/AR

Frequently diagnosed in utero. Infants present with multiple intrauterine fractures at different stages of healing, deformed limbs and occasionally hydrops fetalis. Sclerae are blue. Condition is lethal perinatally due to the fragile skeleton.

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Types 3 and 4 constitute severe deforming OI. Birth length is normal. Sclerae are white. Multiple fractures form birth lead to significant deformity and may necessitate wheelchair use as an adult. There is significant short stature and severe limb deformity with thoracic deformity (pectus carinatum) and kyphoscoliosis. Abnormal cranial molding results in characteristic triangular shaped facies and frontal bossing. Pulmonary insufficiency from thoracic and spinal deformity is a leading cause of death.

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26. Abnormal mineralisation group Hypophosphatasia

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Osteogenesis imperfecta, perina- The nosology retains the original tal lethal form (OI type 2) Sillence classifiOsteogenesis imperfecta, progres- cation to classify sively deforming type (OI type 3) OI severity, however it frees it Osteogenesis imperfecta, moder- from any direct molecular referate form (OI type 4) ence as many gene abnormaliOsteogenesis imperfecta, with calcification of the interosseous ties have been membranes and/or hypertrophic found to cause OI, and variacallus (OI type 5) tion arising from abnormaities at the same loci can produce different phenotypes.

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24. Increased bone density group with metaphyseal and/or diaphyseal involvement Diaphyseal dysplasia Camurati- TGFβ1/ Engelmann transforming growth factor beta 1

Hypophosphataemic rickets

ALPL/Alkaline AR/AD phosphatase, tissue non-specific (TNSALP) PHEX/X-linked XLD hypophosphataemic membrane protease

A type of rickets. Characteristic radiographic features include bilateral symmetrical anterolateral femoral and tibial bowing with metaphyseal cupping, lucency and flaring and physeal widening. Mucopolysaccharidoses result in a proportionate dwarfism with presence of complex sugars in urine. Newborns with mucopolysaccharidosis appear healthy at birth.

27. Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group) Mucopolysaccharidosis type 1 (Hurler’s syndrome)

Features are similar to rickets. Investigations demonstrate low alkaline phosphatase and increased urinary phosphethanolamine.

IDA/alpha-1iduronidase

AR

Severe form. Growth and mental development slows between 6–18 months. Developmental milestones such as walking are delayed. Children develop severe joint stiffness, have significant learning impairment, genu valgum, thoracolumbar kyphosis and a characteristic facial appearance with cloudy cornea. Odontoid hypoplasia may be a feature. Death usually occurs from respiratory or cardiac complications in childhood. Bone marrow transplant may increase survival. Diagnosis may be confirmed by the presence of dermatan/heparin sulphate in the urine.

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M.D. Sewell et al. / Genetic skeletal dysplasias: A guide to diagnosis and management Table 1, continued Gene defect/ Inheritance Distinguishing features abnormal protein IDS/Iduronate-s- XLR Typically affects boys. Children demonstrate severe learning impairment sulphatase with a clear cornea, macrocephaly and coarse facial features. Significant joint stiffness and contractures are present by pre-school age. Diagnosis may be confirmed by the presence of dermatan/heparin sulphate in the urine.

Mucopolysaccharidosis type 3 (Sanfilippo’s syndrome)

HSS/Heparin sul- AR phate sulphatase

Learning impairment and reduced growth rate occurs after 2–3 years. Children have a clear cornea, coarse facial features and are usually wheelchairbound by teenage years. Diagnosis may be confirmed by the presence of heparin sulphate in the urine.

Mucopolysaccharidosis type 4 (Morquio’s syndrome)

AR GALNS/ Galactosamine-6sulphate sulphatase

Commonest type. This is a short-trunk dwarfism. Individuals have normal intelligence and a cloudy cornea. Facial features are usually normal. The neck is short and odontoid hypoplasia, atlanto-axial instability, thoracic kyphoscoliosis, genu valgum, barrel chest and pectus carinatum may be present. It usually presents around the age of 2–3 years with non-specific symptoms such as difficulty climbing stairs, impaired exercise tolerance and leg aching. Spine radiograph will show platyspondyly and later kyphoscoliosis. Diagnosis may be confirmed by the presence of keratan sulphate in the urine.

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Genetic group/name of skeletal disorder Mucopolysaccharidosis type 2 (Hunter’s syndrome)

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Multiple bony osteochondroma occur throughout the skeleton. They are most noticeable around the knee, ankle and proximal humerus. Radiographically they arise in the metaphysis and grow away from the epiphysis. They may cause slowed growth, limb deformity, movement restriction and leg length discrepancy. Malignant change to chondrosarcoma occurs in 1%.

GNAS1/Guanine sporadic nucleotidebinding protein, alpha stimulating activity subunit 1

Neurofibromatosis type 1 (NF1)

NF1/ neurofibromin

Bone is replaced by fibrous tissue with small islands of calcification and a ‘ground glass appearance’ on radiographs. Usually presents in second decade with a progressive deformity such as a ‘shepherd’s crook’ deformity of the proximal femur caused by coxa vara, or pathological fractures through lesions. McCune Albright syndrome describes polyostotic fibrous dysplasia, precocious puberty and café-au-lait spots.

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Fibrous dysplasia, polyostotic form

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29. Disorganised development of skeletal components group Multiple hereditary cartilaginous EXT1 or EXT2/ exostoses (types 1–2) Exostosin-1 or 2

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28. Osteolysis group

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AD

Diagnosed when two or more of the following are present: 1) > 5 café-aulait spots over 5 mm in a child or > 15 mm in an adult, 2) skeletal dysplasia such as tibial pseudarthosis/sphenoid dysplasia/kyphoscoliosis, 3) single plexiform neurofibroma, or > 1 neurofibroma of any type, 4) 1st degree family history, 5) > 2 Lisch nodules (iris hamartoma), 6) optic glioma, 7) axillary or inguinal freckling, or 8) NF1 gene mutation (chr 17).

Not hered- Unilateral osteochondroma affecting the epiphysis only. Lesions stop growitary ing after skeletal maturity.

unknown Enchondromatosis (Ollier’s disease) Enchondromatosis with haemangiomata (Maffuci syndrome)

Multifactorial sporadic

Disorder in which masses containing hyaline cartilage develop in the metaphyses and diaphyses of tubular bones. The masses are continuous with the growth plates and are usually unilaterally distributed. Children may present with bony lumps, limb deformity, growth disturbance and leg length discrepancy. Occasionally pathological fractures occur through lesions. Lesions stop growing after puberty. There is a 30% risk of malignant transformation into a chondrosarcoma in later life.

AD

Proportionate dwarfism that affects bones formed by intramembranous ossification. Children present with a waddling gait from coxa vara or excessive shoulder movements due to clavicular aplasia or hypoplasia. Frontal bossing

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Dysplasia epiphysealis hemimel- unknown ica (Trevor’s disease)

30. Overgrowth syndromes with skeletal involvement 31. Genetic inflammatory/ rheumatoid-like osteoarthropathies 32. Cleidocranial dysplasia and isolated cranial ossification defects group Cleidocranial dysplasia

RUNX2/Runt related transcription factor 2

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Table 1, continued Genetic group/name of skeletal disorder

Gene defect/ Inheritance Distinguishing features abnormal protein may be present. Radiographic features include delayed skull suture closure, persistently open anterior fontanelle, large brachcephalic skull, 11 ribs, posterior wedging of thoracic vertebrae, high narrow iliac wings with hypoplasia of the pubic bones.

33. Craniosynostosis syndromes Apert syndrome

AD FGFR2/ Fibroblast growth factor receptor 2

Premature fusion of skull bones (craniosynostosis) results in facial dysmorphism with underdeveloped jaw, crowded teeth, bulging and wide set eyes, midface hypoplasia and beaked nose. Fingers and toes may also be fused together (syndactyly). Cognitive abilities may be normal or there may be mild-to-moderate learning difficulties. Visual, hearing and dental problems are common.

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35. Dysostoses with predominant vertebral with and without costal involvement

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36. Patella dysostoses

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39. Polydactyly-syndactylytriphalangism group 40. Defects in joint formation and synostoses

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tio and decreased arm span/sitting height ratio [22]. Normal anthropometric ratios change with age: the U/L segment ratio in neonates is 1.7. This decreases to 0.95 at skeletal maturity [2]. Ancillary signs, particularly facial dysmorphism, aid with diagnosis (Table 1). Macrocephaly, frontal bossing, midface hypoplasia (flattened midface) and short upturned noses are characteristic of achondroplasia [20], swollen ear pinnae in diastrophic dysplasia [28], cleft palate and micrognathia in types II and XI collagen disorders and midface hypoplasia with hypoplastic nasal bridge in the chondrodysplasia punctate disorders [15] (Table 1). Deformities of the upper and lower limbs (e.g. trident hand in achondroplasia) and spine (e.g. odontoid hypoplasia in Morquio’s syndrome) also provide phenotypic diagnostic clues.

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FGFR, fibroblast growth factor receptor; COMP, cartilage oligomeric matrix protein; PTHR parathyroid hormone receptor; DTDST, sulphate transport protein; CBFA1, transcription factor for osteocalcin; PEX, gene regulating renal tubular reabsorption of phosphate; AD, autosomal dominant; AR, autosomal recessive; XLR, X-linked recessive; XLD, X-linked dominant.

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4. Investigation

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4.1. Radiological assessment

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A complete ‘genetic skeletal survey’ should be performed which includes anteroposterior (AP) and lat-

eral skull radiographs, AP and lateral whole spine, AP pelvis, AP one arm and one leg with separate AP views of the hands and feet [29]. Radiological abnormalities are best seen on childhood radiographs when the growth plates are open. The first step involves identifying the location of shortening within the limb (rhizomelic, mesomelic, acromelic), and spinal involvement, characterised by vertebral irregularities or platyspondyly (Fig. 1) [29]. The second step involves assessment of epiphyseal, metaphyseal and diaphyseal ossification. Epiphyseal dysplasia is characterised by absent, small, or irregularly ossified epiphyses (Fig. 2). Metaphyseal dysplasia is characterised by irregular, widened or flared metaphyses (Fig. 3). Diaphyseal dysplasia is characterised by diaphyseal widening, sclerosis, cortical thickening, or medullary narrowing or expansion (Fig. 4). Associated spinal involvement denotes a spondylo-epiphyseal-dysplasia (SED), spondylo-metaphyseal-dysplasia (SMD) or spondylo-epimeta-physeal-dysplasia (SEMD). Radiographs should also be analysed for bone age maturation, presence of joint dislocations (e.g. Larson’s syndrome) and abnormal mineralisation (e.g. hypomineralisation in osteo-

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M.D. Sewell et al. / Genetic skeletal dysplasias: A guide to diagnosis and management Table 2 Initial assessment of a patient with short stature When the short stature was recognised: prenatally or later in child’s life Detailed family history and antenatal history Disease specific symptoms Specific orthopaedic and non-orthopaedic complications (psychological, cardiac, renal, gastrointestinal, immunological, neurological and visual)

Examination

Anthropometric measurements: sitting and standing heights upper/lower segment (U/L) ratio head circumference arm span/sitting height ratio Evaluate type of short stature: Proportionate Disproportionate If disproportionate: short limb short trunk If short limb, position of limb shortening: Rhizomelic – proximal segment shortening (humerus/femur) Mesomelic – middle segment shortening (radius/ulna/tibia/fibula) Acromelic – distal segment shortening (hand/foot) Facial dysmorphisms Non-musculoskeletal features: Cardiac malformations Renal Gastrointestinal Immunological Neurological and visual Generic descriptive terms: Diastrophic – twisted Campomelic – curved or bent limb Metatropic – changing Kyphomelic – forward bent Thanotropic – death bringing

Investigations

Radiographs Steps: 1) Assessment of disproportion and spinal involvement 2) Assessment of epiphyseal, metaphyseal and diaphyseal ossification Histology of growth plate tissue Sources: 1) iliac crest biopsy during elective orthopaedic procedures, 2) autopsy from those with a perinatally lethal disorder. Molecular tests (frequently not required) Indicated when the causal gene for a disorder is known and either: 1) the diagnosis is unclear after clinical, radiological, and if possible, histological examination, 2) prenatal diagnosis (chorionic villus sampling or amniocentesis) in at risk foetuses, or, 3) to predict carrier status in families at risk of a recessive disorder

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History

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genesis imperfecta (OI) and hypophosphatasia). Very occasionally pathognomonic features are present such as iliac horns in nail-patella syndrome [30].

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4.2. Histological examination of growth plate tissue

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Most SDs are diagnosed based on clinical and radiographic features alone, however diagnosis should be supplemented whenever possible, by histological examination of the growth plate (Fig. 5) [31,32]. Tissue may be obtained at autopsy in those with a perinatally

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lethal disorder, or iliac crest biopsy in those undergoing elective surgery [2].

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4.3. Molecular diagnosis

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The last 30 years has seen enormous expansion in knowledge concerning the molecular-genetic basis of SDs. Many genes code for extracellular structural matrix proteins in cartilage or bone such as collagens (types I, II, IX, X, XI), proteoglycans (aggrecan, perlecan), matrilin-3 protein (MATN3), and car-

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Fig. 1. Lateral spine radiograph demonstrating platyspondyly with classical rounded, flattened vertebral bodies with anterior beaking (white arrow representing delayed ossification) and wide intervertebral disc spaces in a patient with Morquio’s disease.

Fig. 2. Anteroposterior pelvic radiograph in a six years old child with multiple epiphyseal dysplasia. The epiphyses (white arrows) are small and fragmented representing ossification delay. The spine, metaphyses and diaphyses are normal.

Fig. 3. Long leg radiograph demonstrates metaphyseal dysplasia (white arrows) with preservation of the epiphyses (red arrows) and diaphysis in a patient with metaphyseal chondrodysplasia. The metaphyses are irregular, flared and widened. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/ BMR-140558)

tilage oligomeric matrix protein (COMP) [3,33]. Mutations may also occur in genes for intracellular structural proteins, transcription factors, and RNA processing molecules, amongst others [2]. Molecular diagnosis for many SDs is now possible but is a complex process. Mutations in the same gene can produce different phenotypes (e.g. FGFR3 mutations can cause perinatally lethal thanatophoric dysplasia, and non-lethal achondroplasia), and mutations in different genes can produce the same phenotype (e.g. multiple epiphyseal dysplasia (MED) can be caused by mutations in COMP, genes for type IX collagen, MATN3, diastrophic dysplasia sulphate transporter (DTDST), and multiple currently unidentified genes [34–39]). Genetic testing should only be requested in consultation with a geneticist. Molecular diagnosis is indicated when the causal gene for a disorder is known and 1) the diagnosis is unclear after clinical, radiological, and if possible, histological examination, 2) for prenatal diagnosis in at risk

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Table 3 Skeletal dysplasias that are lethal in the perinatal and neonatal periods

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Osteogenesis imperfecta type II (commonest) Thanatophoric dysplasia (2nd commonest) Achondrogenesis Atelosteogenesis Campomelic dysplasia Chondrodysplasia punctate (lethal variants) Metatropic dysplasia (lethal variants) Pacman dysplasia Perinatally lethal hypophosphatasia Short-rib polydactyly syndromes

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Fig. 5. Histological section of the growth plate, indicating the zones affected by different skeletal dysplasia: A, resting zone affected in diastrophic dysplasia, B, proliferative zone affected in achondroplasia, C, hypertrophic zone affected in mucopolysaccaridoses, D, primary spongiosa affected in metatropic dysplasia. (Colours are visible in the online version of the article; http://dx.doi.org/ 10.3233/BMR-140558)

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Fig. 4. Lateral tibial radiograph of a patient with Camurati-Engelmann disease (diaphyseal dysplasia). The diaphysis (white arrow) is widened, cortical thickening is present and the marrow space is reduced. The metaphyses and epiphyses are unaffected.

foetuses (by chorionic villus sampling or amniocentesis), or 3) to predict carrier status in families at risk of a recessive disorder [2,39]. In prenatal diagnosis, molecular testing is rarely helpful during the pregnancy for diagnostic/prognostic purposes due to frequent lack of genotype-prognostic correlation. Instead the rationale for prenatal molecular testing are 1) to inform parents early, those who have had a first baby with a severe SD and a recurrence risk, or 2) to confirm the diagnosis (in combination with foetal/newborn radiographs) those with a lethal dysplasia that has been identified during the pregnancy. In those at risk of recessive disorders, molecular diagnosis is important for accurate genetic counselling. For example, in MED, most forms are autosomal dominant; the recurrence risk is very low for phenotypically normal parents (representing the likelihood of a new mutation occurring), and 50% for the

child’s offspring. The DTDST form is recessive; the recurrence risk for phenotypically normal parents is higher (25%) [40].

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Management is multidisciplinary and requires a number of specialists to address specific complications associated with each disorder, for example cardiac malformations in Larsen syndrome [12], shortrib polydactyly disorders [41], and chondroectodermal dysplasia [10,14]. Table 4 outlines management principles. For those with a small chest circumference, respiratory support and follow-up are essential. Children should be screened regularly for hearing and visual impairment. Observational studies have shown healthrelated quality of life (QoL) for adolescents with chondrodysplasias is lower than age-matched controls, particularly for mobility, physical appearance, schools and hobbies, and friends [42]. Pain should be specifically asked about, as it is a frequent cause of reduced QoL. Whilst children may suffer from multi-system disorders, musculoskeletal complications predominate and are the focus of this review.

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Table 4 Management principles [7] Clinical, radiological and (if possible) histology. Occasionally molecular tests.

Genetic counselling

Recurrence risk and reproductive options

Psychological support and rehabilitative therapy

Orthotic prescriptions (walking sticks, shoe raises, etc.)

Medical treatments

Bisphosphonates increase bone mineral density and may reduce fracture risk in osteogenesis imperfecta and other disorders of bone density Role of growth hormone controversial

Management of complications

Treatment principles for orthopaedic complications: Prevent or correct limb deformity Stabilise lax joints Prevent fracture in weak bones Equalise limb lengths Joint replacement for arthritis Decompress, realign and stabilise the spine to prevent deformity and neurological injury

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Medical treatments can be directed at minimising complications such as fractures, or increasing final height through the use of recombinant human growth hormone (GH). In children with severe OI, Glorieux et al [43] showed cyclical administration of intravenous pamidronate decreased bone pain, increased bone mineral density (BMD) and reduced fracture risk with no adverse effects on healing or growth. A recent Cochrane review showed good evidence for oral and intravenous bisphosphonates increasing BMD in IO, however it is was unclear whether they decreased fractures and bone pain [44]. The current treatment recommendations for OI are to combine a bisphosphonate with calcium and vitamin D supplementation if the child is deficient. The rationale to treat short stature is two-fold; to reduce psychological damage sustained from peer ridicule for being short, and to minimise the participation restriction short stature causes individuals in society [45,46]. GH increases linear growth by stimulating proliferation and differentiation of growth plate chondrocytes and also enhances local production of IGF1 [47]. GH has not been effective at increasing final

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Future avenues include stem cell transplants

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Non-orthopaedic complications: Hearing Vision – Myopia, vitreal or retinal degeneration, glaucoma Dental Speech Respiratory – respiratory support at birth may be needed, obstructive sleep apnoea may require weight reduction, CPAP, adenotonsillectomy Reproductive and Obstetric care – Caesarean section for delivery to minimise risk of spinal injury from cephalopelvic disproportion caused by a large fetal head and C1/2 instability Weight control and secondary effects (e.g. hypertension, diabetes, ischaemic heart disease)

height in children with SD, as children have normal levels of GH and the primary problem is with abnormal bone growth, not lack of GH stimulus [48]. Furthermore GH treatment can worsen body disproportion [49], necessitating surgical limb lengthening [48]. Height may be more reliably increased by surgical limb lengthening, or correction of spinal deformities. GH is rarely indicated in SD.

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Limb problems may result from unstable joints, structural bone weakness with a propensity for fracture, bone deformity and leg length discrepancy. Orthotics are helpful to stabilise joints, particularly in the younger child as a holding procedure without altering the natural history. In OI, a type I collagen gene defect results in a qualitative or quantative abnormality of type I collagen resulting in ‘brittle’ bones that are vulnerable to fracture and secondary deformity. In general, long-term orthoses to prevent fractures are poorly tolerated. Telescopic intramedullary rodding is occasionally used to maintain alignment, reduce fracture risk and allow for continued growth (Fig. 6). Angular bone deformity alters the mechanical axis of the limb (Fig. 7) with resultant failure to distribute

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Fig. 7. Long leg radiographs (A) of an 8 years old boy with pseudoachondroplasia who has undergone previous tibial osteotomies in an attempt to improve leg alignment. The mechanical axis is drawn on the left leg from the centre of the hip to the centre of ankle. It should pass through the centre of the knee. In this child it passes lateral to the knee, as a valgus deformity (knock-knee) is present. Mechanical axis malalignment coupled with abnormal cartilage from the dysplasia will result in accelerated knee arthritis unless the deformity is corrected. The child underwent circular frame corrective osteotomy on the left tibia (B) and now has a normal mechanical access passing through the centre of the knee (white line). The child is currently undergoing the same treatment for the right leg. The tibia has been fractured to enable lengthening, in addition to deformity correction.

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load evenly through the articular cartilage. This predisposes to premature osteoarthritis. Deformed bones can be realigned by corrective osteotomy [50]. A corrective osteotomy should realign the mechanical axis of the limb to redistribute weight-bearing load more evenly through the articular cartilage. In theory this slows down the process of premature osteoarthritis, however this has not been shown in long-term studies. Bone deformity and altered growth can result in leg length discrepancy. Longstanding minor discrepancies (< 2 cm) may produce no functional problems, other than subtle abnormality in gait pattern. Shoe raises are helpful for discrepancies of this size. More significant discrepancy (> 2 cm) may result in scoliosis and functional gait imbalance. Epiphysiodesis of the long leg, or lengthening of the short leg may enable equalisation. Surgical lengthening (Fig. 7) procedures may also be used in the upper limb to increase arm length to enable perineal care. Once arthritis is established, joint arthroplasty is indicated which is associated with a higher complication

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Fig. 6. Lateral femur radiograph in a patient with OI type 3 who has undergone telescopic rodding to maintain bony alignment, protect against future fractures and allow continued limb growth. Note the osseus hypomineralisation.

rate and worse functional outcome than arthroplasty in the general population [51–55]. Total hip and knee replacements (THR/TKR) can be technically challenging due to bone deformity, soft tissue contractures, generalised hypotonia and ligament laxity (Fig. 8) [52, 53]. For these reasons, THR/TKR in this group has a higher complication rate with greater risk of revision than in the primary OA group. Very occasionally THR/TKR are required for pain in adolescents.

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Spinal problems are common and may affect anywhere from the foramen magnum to sacrum. Spinal manifestations include platyspondyly, odontoid hypoplasia, atlanto-axial instability, cervical kyphosis, foramen magnum stenosis, scoliosis, kyphoscoliosis, thoracolumbar kyphosis, and lumbar hyperlordosis [56]. In children, instability is frequently the problem particularly at the atlanto-axial articulation (C1/2). This may cause myelopathy, quadriplegia and sudden death and

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Table 5 Skeletal dysplasias commonly associated with atlanto-axial (C1/2) instability [2]

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Chondrodysplasia punctata: Conradi-Hunermann, rhizomelic types, and tibial-metacarpal types Diastrophic dysplasia Larsen syndrome Metaphyseal chondrodysplasia (Mckusick type) Metatropic dysplasia Mucopolysaccharidoses (Morquio’s) Pseudoachondroplasia Type II collagen group disorders including spondyloepiphyseal dysplasias (SED) (congenita, tarda and Kniest dysplasia forms) Spondylo-epi-metaphyseal dysplasias (SEMDs) Spondylometaphyseal dysplasia (SMD) – corner fracture (Sutcliffe) and Kozlowski types

Fig. 9. Lateral flexion cervical spine radiograph demonstrating atlanto-axial (C1/2) instability in a child with Morquio’s disease. The C1 vertebrae (short arrow) has translated forwards on the C2 vertebrae (long arrow) and is pressing on the spinal cord. The child presented with developmental delay.

is a frequent cause of delayed motor milestones [57, 58]. Instability results from structural abnormalities in the vertebrae such as odontoid hypoplasia and platyspondyly, ligament laxity and muscle hypotonia. Sequential flexion and extension views are recommended in all children with SD that affect the cervical spine to detect instability (Fig. 9) (Table 5). Significant instability or evidence of cord compression mandates C1/2 stabilisation [59]. Occasionally cervical kyphosis may be seen in children, particularly in association with Larsen’s syndrome and diastrophic dysplasia. The kyphosis is usually evident at birth. In diastrophic dysplasia the majority resolve as the child develops head control [60].

Progressive kyphosis > 60◦ or neurological symptoms are indications for posterior spinal fusion. Patients with achondroplasia are prone to developing a variety of spinal problems including foramen magnum stenosis, spinal stenosis and thoracolumbar kyphosis (Fig. 10) [61]. Foramen magnum stenosis may present as motor delay, hypotonia, apnoeic attacks or sudden infant death. MRI with CSF flow studies identifies the stenosis for which foramen magnum decompression is effective [62]. Thoracolumbar kyphosis may result in lower limb flexion contractures, neurologic injury and spinal stenosis. In children prevention by activity modification (avoidance of unsupported sitting, and sitting at an angle > 60◦ ) and bracing can

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Fig. 8. Long leg radiographs of an adult with pseudoachondroplasia with advanced osteoarthritis of both hips. The mechanical axes are malaligned and the femoral necks are significantly anteverted, making total hip replacement technically challenging. 334 335 336 337 338 339 340 341 342 343 344 345 346 347

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low specific genetic counselling. There are an increasing number of medical and surgical treatments available requiring a multidisciplinary approach.

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[3] Fig. 10. T2 sagittal MRI (A) of a patient with achondroplasia shows thoracolumbar kyphosis with an apex at L1 (white arrow). T2 axial MRI (B) demonstrates conus compression (white arrow) at this level. The patient was reporting weak legs and bladder dysfunction. Note the short pedicles (red arrow), which are common in achondroplasia. (Colours are visible in the online version of the article; http://dx.doi.org/10.3233/BMR-140558)

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be effective [63]. Bracing is technically difficult with a short trunk, does not always prevent progression and imposes difficulties with activities of daily living, but remains an option if the curve is partially correctable. Surgery is indicated for progressive thoracolumbar kyphoses > 50◦ or those with neurologic injuries [56]. In older patients spinal stenosis occurs which is exacerbated by the thoracolumbar kyphosis. This usually requires surgical decompression [67]. Childhood thoracolumbar kyphoscoliosis may also be seen in SED, SEMD, pseudoachondroplasia, the mucopolysaccaridoses, metatropic dysplasia and the chondrodysplasia punctata group. Kyphotic deformities in SED, pseudoachondroplasia and the mucopolysaccaridoses may resolve spontaneously or with early brace treatment. In the chondrodysplasia punctata group, SEMD and metatropic dysplasia, deformities tend to be more severe and progressive requiring surgical decompression, realignment and stabilisation. This surgery is associated with a high risk of paraplegia, respiratory compromise and mortality.

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5. Conclusion The SDs are a large, heterogeneous group of genetic disorders that typically present with short stature in childhood or early-onset arthritis in adulthood. Accurate diagnosis based upon clinical, radiographic and histological features is important to predict final height, expected complications and treatment, and al-

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Ain MC, Shirley ED. Spinal fusion for kyphosis in achondroplasia. J Pediatr Orthop 2004; 24: 541-45. Lutter LD, Langer LO. Neurological symptoms in achondroplastic dwarfs – surgical treatment. JBJS (Am) 1977; 59: 87-92. Pyeritz RE, Sack GH Jr, Udvarhelyi GB. Thoracolumbar laminectomy in achondroplasia: Longterm results in 22 patients. Am J Med Genet 1987; 28: 433-44. Ain MC, Shirley ED, Pirouzmanesh A, et al. Postlaminectomy kyphosis in the skeletally immature achondroplast. Spine 2006; 31: 197-201. Farmer KW, Brinkley MF, Skolasky RL, et al. Lumbar fusion in achondroplasia. Does fusion to the sacrum affect function? J Pediatr Orthop 2009; 29: 476-80.

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