Skeletal Dysplasia Clinical Presentation
- Author: Harold Chen, MD, MS, FAAP, FACMG; Chief Editor: Luis O Rohena, MD more...
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Family history in skeletal dysplasia
- A complete and accurate family history is essential for evaluation of the nature and inheritance pattern of skeletal dysplasia.
- Histories (including spontaneous abortions or stillbirths), medical records, photographs, and radiographs of affected individuals should be carefully studied for clues to the nature of skeletal dysplasia.
- Parents, siblings, and other relatives should be carefully examined for mild manifestations of the disorder due to variable clinical penetrance and expressivity.
- Multiple affected siblings, normal-appearing parents, and/or consanguinity favor an autosomal recessive mode of inheritance.
- An affected parent (or advanced paternal age in a sporadic case) suggests autosomal dominant inheritance.
- Multiple spontaneous abortions or stillbirths in a family with only female members affected suggest an X-dominant mode of inheritance.
- Affected male siblings and maternal uncles suggest an X-recessive disorder.
Pregnancy and birth histories
- Maternal hydramnios is probably the most significant event associated with fetal skeletal dysplasia during pregnancy.
- Fetal hydrops is frequently observed.
- Fetal activity may be decreased in the lethal types of skeletal dysplasia.
- Maternal usage of warfarin or phenytoin may induce stippling of the epiphyses, resembling the skeletal dysplasia chondrodysplasia punctata.
- When an infant affected with skeletal dysplasia has died before or shortly after birth, lethal chondrodysplasias should be considered. Lethal types of congenital skeletal dysplasia include achondrogenesis, homozygous achondroplasia, chondrodysplasia punctata (recessive form), camptomelic dysplasia, congenital lethal hypophosphatasia, perinatal lethal type of osteogenesis imperfecta, thanatophoric dysplasia, and short-rib polydactyly syndromes.
- Disproportionately short stature (short limbs or short trunk), delayed motor milestone, and airway obstruction may be noted.
- Pain, deformity, and minor or major neural deficits, such as paraparesis and quadriparesis, can be caused by spinal disorders.
- Other skeletal anomalies and functional disturbances include large head with hydrocephalus and bowlegs with waddling gaits. Neurologic complications can be related to atlantoaxial instability, cervical kyphosis, or thoracolumbar kyphosis.
Anthropometric parameters should be compared with the gestational age for the newborn or the chronologic age of the patient, considering appropriate racial, ethnic, socioeconomic, and perinatal factors. To detect disproportionately short stature, anthropometric measurements should include the upper-to-lower segment ratio and arm span.
Diagnosis of short-limb skeletal dysplasia is based on the most severely affected segment of the long bone.
Rhizomelic shortening (short proximal segments [eg, humerus, femur]) is present in patients with achondroplasia, hypochondroplasia, the rhizomelic type of chondrodysplasia punctata, the Jansen type of metaphyseal dysplasia, spondyloepiphyseal dysplasia (SED) congenita, thanatophoric dysplasia, atelosteogenesis, diastrophic dysplasia, and congenital short femur.
Mesomelic shortening (short middle segments [eg, radius, ulna, tibia, fibula]) includes the Langer and Nievergelt types of mesomelic dysplasias, Robinow syndrome, and Reinhardt syndrome.
Acromelic shortening (short distal segments [eg, metacarpals, phalanges]) is present in patients with acrodysostosis and peripheral dysostosis.
Acromesomelic shortening (short middle and distal segments [eg, forearms, hands]) is present in patients with acromesomelic dysplasia.
Micromelia (shortening of extremities involving entire limb) is present in achondrogenesis, fibrochondrogenesis, Kniest dysplasia, dys-segmental dysplasia, and Roberts syndrome.
Diagnosis of the short trunk variety includes Morquio syndrome, Kniest syndrome, Dyggve-Melchior-Clausen disease, metatrophic dysplasia, SED, and spondyloepimetaphyseal dysplasia (SEMD).
Certain clinical features may be of value as diagnostic indicators, although they may not be specific or consistent.
Skeletal dysplasias associated with mental retardation can be broadly categorized in the following terms according to etiology or pathogenesis:
- CNS developmental anomalies - Orofaciodigital syndrome type 1 (hydrocephaly, porencephaly, hydranencephaly, agenesis of corpus callosum) and Rubinstein-Taybi syndrome (microcephaly, agenesis of corpus callosum)
- Intracranial pathologic processes - Craniostenosis syndromes (pressure) and thrombocytopenia-radial aplasia syndrome (bleeding)
- Neurologic impairment - Dysosteosclerosis (progressive cranial nerve involvement) and mandibulofacial dysostosis (deafness)
- Chromosome aberrations - Autosomal trisomies
- Primary metabolic abnormalities - Lysosomal storage diseases
- Other disorders - Chondrodysplasia punctata, warfarin embryopathy (teratogen), and cerebrocostomandibular syndrome (hypoxia)
- Disproportionately large head - Achondroplasia, achondrogenesis, and thanatophoric dysplasia
- Cloverleaf skull - Thanatophoric dysplasia, Apert syndrome, Carpenter syndrome, Crouzon syndrome, and Pfeiffer syndrome
- Caput membranaceum - Hypophosphatasia and osteogenesis imperfecta congenita
- Multiple wormian bones - Cleidocranial dysplasia and osteogenesis imperfecta
- Craniosynostosis - Apert syndrome, Crouzon syndrome, Carpenter syndrome, other craniosynostosis syndromes, and hypophosphatasia
- Congenital cataract - Chondrodysplasia punctata
- Myopia - Kniest dysplasia and SED congenita
Mouth - Bifid uvula and high arched or cleft palate (as in Kniest dysplasia), SED congenita, diastrophic dysplasia, metatrophic dysplasia, and camptomelic dysplasia
Ears - Acute swelling of the pinnae (as in diastrophic dysplasia)
Radial ray defects - Trisomy 18; trisomy 13; vertebral, anal, cardiac, tracheal, esophageal, renal, limb (VACTERL) syndrome; Fanconi anemia; Cornelia de Lange syndrome; Holt-Oram syndrome; Townes-Brock syndrome; Okihiro syndrome, Aase syndrome; acrofacial dysostosis; Levy-Hollister syndrome; TAR syndrome, Roberts syndrome; and Baller-Gerold syndrome.
- Preaxial - Chondroectodermal dysplasia and short-rib polydactyly syndromes (frequently in Majewski syndrome, rarely in Saldino-Noonan syndrome)
- Postaxial - Chondroectodermal dysplasia, lethal short-rib polydactyly syndromes, and Jeune syndrome
Hands and feet
- Hitchhiker thumb - Diastrophic dysplasia
- Clubfoot - Diastrophic dysplasia, Kniest dysplasia, and osteogenesis imperfecta
- Hypoplastic nails - Chondroectodermal dysplasia
- Short and broad nails - McKusick metaphyseal dysplasia
Joints - Multiple joint dislocations, as in Larsen syndrome and otopalatodigital syndrome
Long bone fractures (as in osteogenesis imperfecta syndromes, hypophosphatasia, osteopetrosis, and achondrogenesis type I)
- Long or narrow thorax - Asphyxiating thoracic dysplasia, chondroectodermal dysplasia, and metatrophic dysplasia
- Pear-shaped chest - Thanatophoric dysplasia, short-rib polydactyly syndromes, and homozygous achondroplasi
- Atrial septal defect or single atrium - Chondroectodermal dysplasia
- Patent ductus arteriosus - Lethal short-limbed skeletal dysplasias
- Transposition of the great vessels - Majewski syndrome
Skeletal dysplasia is a heterogeneous group of disorders characterized by abnormalities of cartilage and bone growth. Their modes of inheritance are heterogeneous (ie, autosomal recessive, autosomal dominant, X-linked recessive, or X-linked dominant).
Skeletal dysplasias with known molecular bases are as follows:
Achondroplasia group: Mutations in the fibroblast growth factor receptor 3 gene ( FGFR3) cause achondroplasia (MIM 100800), hypochondroplasia (MIM 146000), thanatophoric dysplasia (MIM 187600), and other FGFR3 disorders [Muenke syndrome (MIM 602849) and lacrimo-auriculo-dento-digital syndrome (MIM 149730).
Diastrophic dysplasia group: Mutations in the diastrophic dysplasia sulfate transporter gene ( DTDST) cause diastrophic dysplasia, achondrogenesis type IB, and atelosteogenesis type II.
Langer mesomelic dysplasia (LMD) and Leri-Weill dyschondrosteosis (LWDC): SHOX nullizygosity results in Langer mesomelic dysplasia, and SHOX haploinsufficiency leads to Leri-Weill dyschondrosteosis. Turner syndrome and idiopathic short stature are also associated with SHOX deficiency.
Type II collagenopathies: Mutations in the procollagen II gene ( COL2A1) cause achondrogenesis type II (Langer-Saldino dysplasia), hypochondrogenesis (a milder allelic variant of achondrogenesis), Kniest dysplasia, SED congenita, SEMD Strudwick type, SED with brachydactyly, mild SED with premature onset arthrosis, and Stickler dysplasia (hereditary arthro-ophthalmopathy).
Type XI collagenopathies: Mutations in procollagen XI genes ( COL11A1 and COL11A2) cause Stickler dysplasia and otospondylomegaepiphyseal dysplasia.
Multiple epiphyseal dysplasias and pseudoachondroplasia: Mutations in the cartilage oligomatrix protein gene ( COMP) cause multiple epiphyseal dysplasias and pseudoachondroplasia.
Chondrodysplasia punctata (stippled epiphyses group): Genes that encode the peroxisomal biogenesis factors (PEX) are responsible for rhizomelic chondrodysplasia punctata and Zellweger syndrome. Mutations in the X-linked dominant chondrodysplasia punctata gene ( CPXD) cause the Conradi-Hunermann type of chondrodysplasia punctata. Mutations in the X-linked recessive chondrodysplasia punctata gene ( CPXR) cause the X-linked recessive type of chondrodysplasia punctata. Mutations in the arylsulfatase E gene ( ARSE) cause the brachytelephalangic type of chondrodysplasia punctata.
Metaphyseal dysplasias: A mutation in the gene encoding the parathyroid hormone/parathyroid hormone–related polypeptide receptor ( PTHR) is responsible for the Jansen type of metaphyseal dysplasia. Mutations in the procollagen X gene ( COL10A1) cause the Schmid type of metaphyseal dysplasia. Mutations in the adenosine deaminase gene ( ADA) cause the adenosine deaminase type of metaphyseal dysplasia.
Acromelic and acromesomelic dysplasias: Mutations in the gene encoding the cartilage-derived morphogenic protein-1 gene ( CDMP1) cause Grebe dysplasia, Hunter-Thompson dysplasia, and brachydactyly type C. Mutations in the gene coding for the guanine nucleotide-binding protein of the adenylate cyclase a-subunit ( GNAS1) cause pseudohypoparathyroidism (Albright hereditary osteodystrophy).
Dysplasias with prominent membranous bone involvement: Mutations involving the transcription core binding factor a 1 -subunit gene ( CBFA1) cause cleidocranial dysplasia.
Bent bone dysplasia group: Mutations in the gene coding for the SRY-box 9 protein ( SOX9) cause camptomelic dysplasia.
Dysostosis multiplex group: Specific gene mutations cause different types of mucopolysaccharidosis, fucosidosis, mannosidosis, aspartylglycosaminuria, G M1 gangliosidosis, sialidosis, sialic acid storage disease, galactosialidosis, multiple sulfatase deficiency, and mucolipidosis types II and III.
Dysplasias with decreased bone density: Mutations in the procollagen I genes ( COL1A1, COL1A2) cause various types of osteogenesis imperfecta.
- Type I (a dominant form with blue sclera)
- Type II (a perinatal lethal form)
- Type III (a progressively deforming type with normal sclerae)
- Type IV (a dominant form with normal sclerae)
Dysplasias with defective mineralization: Mutations in the liver alkaline phosphatase gene ( ALPL) cause perinatal lethal and infantile forms of hypophosphatasia. Mutations in the X-linked hypophosphatemia gene ( PHEX) cause hypophosphatemic rickets. Mutations in the parathyroid calcium-sensing receptor gene ( CASR) cause neonatal hyperparathyroidism and transient neonatal hyperparathyroidism.
Increased bone density without modification of bone shape: Mutations in the carbonic anhydrase II gene ( CA2) cause osteopetrosis with renal tubular acidosis. Mutations in the gene encoding cathepsin K ( CTSK) cause pyknodysostosis.
Disorganized development of cartilaginous and fibrous components of the skeleton: Mutations in exostosis genes ( EXT1, EXT2, EXT3) cause multiple cartilaginous exostoses. Mutations in the guanine nucleotide-binding protein a-subunit gene ( CNAS1) cause fibrous dysplasia (McCune-Albright and others). The bone morphogenic protein 4 gene ( BMP4) is overexpressed in fibrodysplasia ossificans progressiva.
Skeletal dysplasias and disease genes associated with osteoarthritis: These mutations cause SED congenita ( COL2A1), SED tarda ( COL2A1, SEDL), Stickler dysplasia ( COL2A1, COL11A1 - A2), pseudoachondroplasia ( COMP), MED ( COMP, COL9A1 - A3, MATN3, DTDST), and progressive pseudorheumatoid chondrodysplasia ( WISP3).
Mutations in osteopetrosis: These mutations cause type I ( LRP5), type II ( CLCN7), Van Buchem disease ( SOST), sclerostenosis ( SOST), autosomal recessive osteopetrosis ( OSTM1, TCIRG1, CLCN7), and osteopetrosis with renal tubular acidosis ( CA2)
Mutations in osteoporosis: These mutations cause osteoporosis-pseudoglioma syndrome ( LRP 5) and familial expansile osteolysis ( RANK).
Mutations in craniosynostosis: These include mutations in FGFR1 (osteoglophonic dysplasia, Pfeiffer syndrome), FGFR2 (Apert syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, nonclassifiable and variable craniosynostosis), FGFR3 (thanatophoric dysplasia, type I and type II, crouzondermoskeletal syndrome, Muenke syndrome, hypochondroplasia), TWIST (Saethre-Chotzen syndrome), MSX2 (Boston type craniosynostosis), EFNB1 (craniofrontonasal syndrome), EFNA 4 (nonsyndromal coronal synostosis), POR (Antley-Bixler syndrome), and ALPL (hypophosphatasia, particularly infantile type).
Mutations in IHH gene: These mutations cause brachydactyly type A1 and acrocapitofemoral dysplasia.
Mutations in PTHR1: These mutations cause Jansen metaphyseal chondrodysplasia, Blomstrand chondrodysplasia, Eiken syndrome, and multiple enchondromatosis, Ollier type.
Mutations in FLNA: These mutations cause otopalatodigital syndrome type I and II, frontometaphyseal dysplasia, and Melnick-Needle syndrome.
Molecular–pathogenetic classification of the skeletal dysplasias is as follows:[13, 14]
Defects in extracellular structural proteins
- COL1A1, COL1A2 - Osteogenesis imperfecta
- COL2A1 - Achondrogenesis 2, hypochondrogenesis, SED congenita, SEMD, Kniest, Stickler, familial osteoarthritis
- COL9A1, COL9A2, COL9A3 - Multiple epiphyseal dysplasia (MED)
- COL10A1 - Metaphyseal dysplasia Schmid
- COL11A1, COL11A2 - Oto-spondylo-megaepiphyseal dysplasia (OSMED); Stickler (variant), Marshall syndrome
- COMP - Pseudoachondroplasia, MED
- MATN3 - Multiple epiphyseal dysplasia
- Perlecan - Schwartz-Jampel type 1; dyssegmental dysplasia
Defects in metabolic pathways
- Tissue nonspecific alkaline phosphatase (TNSALP) - Hypophosphatasia (several)
- Pyrophosphate transporter (ANKH) - Craniometaphyseal dysplasia
- Diastrophic dysplasia sulfate transporter (DTDST) - Achondrogenesis 1B, atelosteogenesis 2, diastrophic dysplasia, autosomal recessive MED (rMED)
- Phosphoadenosine-phosphosulfate-synthase 2 (PAPSS2) - SEMD Pakistani type
- Chondroitin 6-O-sulfotransferase-1 (CHST3) - SEMD Omani type
Defects in folding, processing, transport, and degradation of macromolecules
- Sedlin (unknown function) - X-linked SED (SED-XL)
- Cathepsin K (lysosomal proteinase) - Pycnodysostosis
- Lysosomal acid hydrolases and transporters - Mucopolysaccharidoses, oligosaccharidoses, glycoproteinoses
- Targeting system for lysosomal enzymes (GlcNAc-1-phosphotransferase) - Mucolipidosis type II and III
- Matrix metalloproteinase 2 (MMP2) - Torg type osteolysis
- Tubulin chaperonin E - Kenney-Caffey and Sanjod-Sakati syndromes (TBCE)
- EXT1, EXT2 - Multiple exostoses syndrome types 1 and 2
- SH3BP2 (c-Abl -binding protein) - Cherubism
Defects in hormones, growth factors, receptors, and signal transduction
- FGFR1 - Craniosynostosis syndromes (Pfeiffer syndrome)
- FGFR2 - Craniosynostosis syndromes (Apert syndrome, Crouzon syndrome, Pfeiffer syndrome)
- FGFR3 - Thanatophoric dysplasia, achondroplasia, hypochondroplasia,
- SADDAN - Craniosynostosis syndromes
- ROR-2 (orphan receptor tyrosine kinase) - Autosomal recessive, Robinow syndrome; autosomal dominant, Brachydactyly type B
- PTH/PTHrP receptor - Metaphyseal dysplasia, Jansen syndrome (activating mutations); Blomstrand lethal dysplasia (inactivating mutation)
- Stimulatory Gs protein of adenylate cyclase (GNAS1) - Pseudohypoparathyroidism (Albright hereditary osteodystrophy) with constitutional haploinsufficiency mutations; McCune–Albright syndrome with somatic mosaicism for activating mutations
Defects in nuclear proteins and transcription factors
- SOX9 - Camptomelic dysplasia
- TRPS1 (zinc-finger gene) - Tricho-rhino-phalangeal syndromes
- CBFA-1 (runt-type transcription factor) - Cleidocranial dysplasia
- LXM1B (LIM homeodomain protein) -Nail-patella syndrome
- SHOX (short stature—homeobox gene) - Leri–Weill dyschondrosteosis, Turner syndrome
- EVC (Leucine-zipper gene) - Autosomal recessive, chondroectodermal dysplasia (Ellis-van Creveld); autosomal dominant, Weyers acrodental dysostosis
Defects in RNA processing and metabolism
- RMRP -Cartilage-hair-hypoplasia
- SDDS - Shwachman–Diamond syndrome
Defects in cytoskeletal proteins
- Filamin A - Otopalatodigital syndromes I and II, frontometaphyseal dysplasia, Melnick-Needles
- Filamin B - Spondylocarpotarsal syndrome, Larsen syndrome, atelosteogenesis I/III, Boomerang dysplasia
Responsible gene identified, but function unknown (Dymeclin - Dyggve–Melchior–Clausen syndrome, Smith–McCort syndrome)
The 2006 Revision of the Nosology and Classification of Genetic Disorders of Bone is as follows (for various disorders under each group, please refer to original reference):
Type 2 collagen group
Type 11 collagen group
Sulphation disorders group
Short-rib dysplasia (with or without polydactyly) group
Multiple epiphyseal dysplasia and pseudoachondroplasia group
Spondylometaphyseal dysplasias (SMD)
Severe spondylodysplastic dysplasias
Moderate spondylodysplastic dysplasias (brachyolmias)
Mesomelic and rhizo-mesomelic dysplasias
Bent bones dysplasias
Slender bone dysplasia group
Dysplasias with multiple joint dislocations
Chondrodysplasia punctata (CDP) group
Neonatal osteosclerotic dysplasias
Increased bone density group (without modification of bone shape)
Increased bone density group with metaphyseal and/or diaphyseal involvement
Decreased bone density group
Defective mineralization group
Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)
Disorganized development of skeletal components group
Cleidocranial dysplasia group
Craniosynostosis syndromes and other cranial ossification disorders
Dysostoses with predominant craniofacial involvement
Dysostoses with predominant vertebral and costal involvement
Brachydactylies (with or without extraskeletal manifestations)
Limb hypoplasia reduction defects group
Defects in joint formation and synostoses
Nosology and classification of genetic skeletal disorders 2010 revision 
Four hundred and fifty-six different conditions were included and placed in 40 groups defined by molecular, biochemical, and/or radiographic criteria. Of these conditions, 316 (2006 revision, 215) were associated with one or more of 226 (2006 revision, 140) different genes. Within a group, disorders with known molecular basis have been listed preceding those with lesser degree of evidence; however, variants of the same disorder have been kept together.
The organization of groups has been further changed in comparison to the 2006 version. Two new groups based on a common affected molecule or biochemical pathway have been created (TRPV4 group and Aggrecan group). The TRPV4 group includes disorders that are relatively common and that constitute a new prototypic spectrum ranging from mild to lethal. Aggrecan is one of the important structural molecules in cartilage and it would not be surprising if more disorders would find their way into this group in the future. Thus, groups 1–8 are based on a common underlying gene or pathway.
Groups 9–17 are based on the localization of radiographic changes to specific bone structures (vertebrae, epiphyses, metaphyses, diaphysis, or combination thereof) or of the involved segment (rhizo, meso, or acro). Groups 18–20 are defined by macroscopic criteria in combination with clinical features (bent bones, slender bones, presence of multiple dislocations). Groups 21–25 and 28 take into account features of mineralization (increased or reduced bone density, impaired mineralization, stippling, osteolysis). Group 27 encompasses the large group of lysosomal disorders with skeletal involvement. Group 29 comprises disorders with so-called abnormal (previously ‘‘anarchic’’) development of skeletal components such as exostoses, enchondromas, and ectopic calcification. It is particularly heterogeneous and may need to be revised in the future with the help of newer molecular data.
Group 23, comprising the osteopetrosis (OP) variants and related disorders, has been expanded following the identification of distinct genetic defects in various variants of osteopetrosis. The diversity of molecular mechanisms involved and the presence of clinical, biochemical and/or histologic features that distinguish between the various OP forms justify the subdivision of the ‘‘OP phenotype’’ in the many subtypes.
Group 25 (osteogenesis imperfecta and decreased bone density group) has had special attention. The Sillence classification, published 30 years ago, provided a first systematic clinical classification and made correlations to the inheritance pattern of individual clinical types.[17, 18]
Today, a surprising genetic complexity of the molecular bases of osteogenesis imperfecta has been revealed, and at the same time the extensive phenotypic variation arising from single loci has been documented clearly. Maintaining tight correlations between "Sillence types" and their molecular basis seemed untenable. The Sillence classification is the prototypic and universally accepted way to classify the degree of severity in osteogenesis imperfecta and is free from any direct molecular reference. Thus, the many genes that may cause osteogenesis imperfecta have been listed separately. The proliferation of "osteogenesis imperfecta types" to reflect each gene separately, advocated by some scholars, is more confusing than helpful in clinical practice.
Group 26 has seen the identification of several novel molecular mechanisms leading to hypophosphatemic rickets.
In Group 29 (disorganized development of skeletal components), neurofibromatosis type 1 (NF1) has been included following the points made by Stevenson and others that although the main clinical features of NF1 are neurologic and cutaneous, the skeletal features are frequent, diagnostically helpful, and clinically relevant.
Groups 30 (overgrowth syndromes with significant skeletal involvement) and Group 31 (genetic inflammatory/rheumatoidlike osteoarthropathies) have been newly added. Group 30 comprises disorders that present as overgrowth syndromes and have a significant skeletal component that is part of the diagnostic criteria for a specific condition. One condition has been tentatively included because of its conspicuous skeletal features;[20, 21] however, this condition remains incompletely delineated.
Group 31 includes disorders with features of inflammation and skeletal involvement. The creation of these two groups has been suggested by the frequent diagnostic overlap between these disorders and primary skeletal disorders as well as by the identification of the genetic basis of such disorders in recent years, allowing for a more precise delineation of the phenotypes.
Finally, groups 32–40 are dedicated to the dysostoses and follow again anatomical criteria (cranium, face, axial skeleton, extremities) with additional criteria reflecting principles of embryonic development such as limb reduction or hypoplasia (proximal-distal growth) versus terminal differentiation and patterning of the digits or joint formation. These groups have seen a marked increase in conditions with identified molecular bases and there are indications of a much larger heterogeneity yet.
A single group, the Brachyolmias (formerly group 13), has been deleted. Following the inclusion of dominant brachyolmia in the TRPV4 group, the few remaining short-trunk disorders have been incorporated in the SED group.
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