Skeletal Dysplasia Clinical Presentation

Updated: Sep 28, 2018
  • Author: Santina A Zanelli, MD; Chief Editor: Luis O Rohena, MD, MS, FAAP, FACMG  more...
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Presentation

History

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.

Clinical history

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.

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Physical

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)

  • Skull

    • 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

    • Large fontanelle, wide sutures - Cleidocranial dysplasia

  • Eyes

    • Congenital cataract - Type II collagenopathies, campomelic dysplasia, and chondrodysplasia punctata,

    • Severe myopia - Type II collagenopathies, particularly Kniest dysplasia and SED congenita

  • Oral cavity

    • Bifid uvula and high arched or cleft palate - Kniest dysplasia, SED congenita, diastrophic dysplasia, metatrophic dysplasia, and camptomelic dysplasia

    • Cleft palate - Type II collagenopathies and campomelic dysplasia

    • Multiple labiogingival frenula - Ellis-van Creveld syndrome [17]

  • Teeth

    • Natal teeth - Ellis-van Creveld dysplasia

    • Dentinogenesis imperfecta - Osteogenesis imperfecta

    • Hypoplasia of dental cementum - Hypophosphatasia

    • Supernumerary teeth - Cleidocranial dysplasia

  • Ears - Acute swelling of the pinnae (as in diastrophic dysplasia)

  • Skin

    • Redundant skin folds - Achondroplasia and hypochondroplasia

    • Ichthyosiform erythroderma - Chondrodysplasia punctata

    • Acanthosis nigricans - Severe achondroplasia and hypochondroplasia

  • 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.

  • Polydactyly

    • 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

  • Nails

    • Hypoplastic nails - Chondrodysplasia punctata-brachytelephalangic type and Elis-van Creveld syndrome,

    • 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)

  • Limb asymmetry - Chondrodysplasia punctata-Conradi-Hunermann type

  • Thorax/ribs

    • Long or narrow thorax - Asphyxiating thoracic dysplasia, chondroectodermal dysplasia, and metatrophic dysplasia

    • Pear-shaped chest - Thanatophoric dysplasia, short-rib polydactyly syndromes, and homozygous achondroplasia

  • Heart

    • Atrial septal defect or single atrium - Chondroectodermal dysplasia

    • Patent ductus arteriosus - Lethal short-limbed skeletal dysplasias

    • Transposition of the great vessels - Majewski syndrome

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Causes

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: [18]

  • 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 a1-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, GM1 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, Crouzonodermoskeletal 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: [19, 20]

  • 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 Sanjad-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

  • 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)

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Complications

Major complications for the most common skeletal dysplasias—achondroplasia and osteogenesis imperfecta—are listed below.

Achondroplasia

Major complications include the following:

  • Risk of cervicomedullary spinal cord compression due to narrow foramen magnum and/or cervical canal
  • Nasal obstruction
  • Thoracolumbar kyphosis and other orthopedic complications
  • Hearing impairment from chronic otitis media
  • Hydrocephalus (uncommon)
  • In adulthood - spinal canal narrowing

Osteogenesis imperfecta

Major complications include bone fractures, bone deformity, and growth deficiency.

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Classification

The 2015 revision of Nosology and Classification of Genetic Skeletal Disorders includes fewer conditions than did the previous edition but lists many new genes. [3]  Overall, 436 genetic skeletal diseases have been organized into 42 groups, with 364 genes identified. The groups are as follows.

FGFR3 chondrodysplasia group

This includes the following conditions:

  • Achondroplasia
  • Thanatophoric dysplasia types 1 and 2
  • Hypochondroplasia
  • Severe achondroplasia with developmental delay and acanthosis nigricans
  • Camptodactyly, tall stature, and hearing loss syndrome

Type 2 collagen group

This includes the following conditions:

  • Achondrogenesis type 2
  • Platyspondylic dysplasia (Torrance type)
  • Hypochondrogenesis
  • SED (congenital)
  • SEMD (Strudwick type)
  • Kniest dysplasia
  • Spondyloperipheral dysplasia
  • Mild SED with premature onset arthrosis
  • SED with metatarsal shortening
  • Stickler syndrome type 1

Type 11 collagen group

This includes the following conditions:

  • Stickler syndrome types 2 and 3
  • Marshall syndrome
  • Fibrochondrogenesis
  • Otospondylomegaepiphyseal dysplasias

Sulphation disorders group

This includes the following conditions:

  • Achondrogenesis type 1B
  • Atelosteogenesis type 2
  • Diastrophic dysplasia
  • MED
  • SEMD (PAPSS2 type)
  • Brachyolmia
  • Chondrodysplasia (Golgi-resident PAP 3'-phosphatase [gPAPP] type)
  • Chondrodysplasia with congenital joint dislocations
  • Ehlers-Danlos syndrome

Perlecan group

This includes the following conditions:

  • Dyssegmental dysplasia (Silverman-Handmaker type)
  • Dyssegmental dysplasia (Rolland-Desbuquois type)
  • Schwartz Jampel syndrome (myotonic chondrodystrophy)

Aggrecan group

This includes the following conditions:

  • SED (Kimberley type)
  • SEMD (Aggrecan type)
  • Familial osteochondritis dissecans

Filamin group

This includes the following conditions:

  • Frontometaphyseal dysplasia
  • Osteodysplasty Melnick-Needles
  • Otopalatodigital syndrome types 1 and 2
  • Terminal osseous dysplasia with pigmentary defects
  • Atelosteogenesis types 1 and 3
  • Larsen syndrome (dominant)
  • Spondylo-carpal-tarsal dysplasia
  • Frank-ter Haar syndrome

TRPV4 group

This includes the following conditions:

  • Metatropic dysplasia
  • SEMD dysplasia (Maroteaux type)
  • Spondylometaphyseal dysplasia (Kozlowski type)
  • Brachyolmia (autosomal dominant type)
  • Familial digital arthropathy with brachydactyly

Ciliopathies with major skeletal involvement

These include the following conditions:

  • Chondroectodermal dysplasia (Ellis-van Creveld)
  • Short rib–polydactyly syndromes types 1/3, 4, and 5
  • Asphyxiating thoracic dysplasia
  • Oral-facial-digital syndrome type 4
  • Cranioectodermal dysplasia types 1 and 2
  • Thoracolaryngopelvic dysplasia

Multiple epiphyseal dysplasia (MED) and pseudoachondroplasia group

This includes the following conditions:

  • Pseudoachondroplasia
  • MED (types 1, 2, 3, 5, 6 and other types)
  • Stickler syndrome (recessive type)
  • Familial hip dysplasia
  • MED with microcephaly and nystagmus

Metaphyseal dysplasias

These include the following conditions:

  • Metaphyseal dysplasia (Schmid, Jansen, and Spahr types)
  • Cartilage-hair hypoplasia (CHH, McKusick type)
  • Metaphyseal dysplasia (CHH-like)
  • Eiken dysplasia
  • Metaphyseal dysplasia with pancreatic insufficiency and cyclic neutropenia (Shwachman-Bodian-Diamond syndrome)
  • Metaphyseal anadysplasia types 1 and 2
  • Metaphyseal dysplasia with maxillary hypoplasia

Spondylometaphyseal dysplasias (SMDs)

These include the following conditions:

  • Spondyloenchondrodysplasia
  • Odontochondrodysplasia
  • SMD (Sutcliffe type or corner fractures type)
  • SMD with cone-rod dystrophy
  • SMD with retinal degeneration (axial type)

Spondyloepimetaphyseal dysplasias (SEMDs)

These include the following conditions:

  • Dyggve-Melchior-Clausen dysplasia
  • Immuno-osseous dysplasia
  • SED (Wolcott-Rallison type)
  • SEMD (Matrilin type)
  • SEMD (short limb–abnormal calcification type)
  • SED tarda X-linked
  • Spondylodysplastic Ehlers-Danlos syndrome
  • SPONASTRIME (spondylar and nasal changes, with striations of the metaphyses) dysplasia
  • Platyspondyly (brachyolmia) with amelogenesis imperfecta
  • CODAS (cerebral, ocular, dental, auricular, and skeletal anomalies) syndrome

Severe spondylodysplastic dysplasias

These include the following conditions:

  • Achondrogenesis type 1A
  • Schneckenbecken dysplasia
  • Spondylometaphyseal dysplasia (Sedaghatian type)
  • Severe spondylometaphyseal dysplasia
  • Opsismodysplasia
  • MAGMAS (mitochondria-associated granulocyte macrophage colony–stimulating factor–signaling gene)-related skeletal dysplasia

Acromelic dysplasias

These include the following conditions:

  • Tricho-rhino-phalangeal dysplasia types 1/3 and 2
  • Acrocapitofemoral dysplasia
  • Geleophysic dysplasia
  • Acromicric dysplasia
  • Weill Marchesani
  • Myhre dysplasia
  • Acrodysostosis
  • Angel-shaped phalango-epiphyseal dysplasia
  • Albright hereditary osteodystrophy

Acromesomelic dysplasias

These include the following conditions:

  • Acromesomelic dysplasia (type Maroteaux)
  • Grebe dysplasia
  • Fibular hypoplasia and complex brachydactyly (Du Pan)
  • Acromesomelic dysplasia with genital anomalies
  • Acromesomelic dysplasia (Osebold-Remondini type)

Mesomelic and rhizo-mesomelic dysplasias

These include the following conditions:

  • Dyschondrosteosis (Leri–Weill)
  • Langer type (homozygous dyschondrosteosis)
  • Omodysplasia
  • Omodysplasia, dominant
  • Robinow syndrome (recessive and dominant types) [21]
  • Mesomelic dysplasia (Kantaputra, Nievergelt, Savarirayan, and Kozlowski-Reardon types)
  • Mesomelic dysplasia with acral synostoses

Campomelic dysplasia and related disorders

These include the following conditions:

  • Campomelic dysplasia
  • Stüve-Wiedemann dysplasia
  • Kyphomelic dysplasia

Slender bone dysplasia group

This includes the following conditions:

  • 3-M syndrome
  • Kenny-Caffey dysplasia
  • Osteocraniostenosis
  • Microcephalic osteodysplastic primordial dwarfism types 1/3 and 2
  • IMAGe (intrauterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita, g enitourinary abnormalities) syndrome
  • Hallermann-Streiff syndrome

Dysplasias with multiple joint dislocations

These include the following conditions:

  • Desbuquois dysplasia
  • Desbuquois dysplasia with short metacarpals and elongated phalanges
  • Desbuquois dysplasia type 2
  • Pseudodiastrophic dysplasia
  • SEMD with joint laxity

Chondrodysplasia punctata (CDP) group

This includes the following conditions:

  • CDP, X-linked dominant (Conradi-Hünermann type)
  • CDP, X-linked recessive (brachytelephalangic type)
  • CHILD (congenital hemidysplasia, ichthyosis, limb defects)
  • Keutel syndrome
  • Greenberg dysplasia
  • Rhizomelic CDP (types 1, 2, and 3)
  • CDP (tibial-metacarpal type)
  • Astley-Kendall dysplasia

Neonatal osteosclerotic dysplasias

These include the following conditions:

  • Blomstrand dysplasia
  • Desmosterolosis
  • Caffey disease
  • Caffey dysplasia
  • Raine dysplasia   

Osteopetrosis and related disorders

These include the following conditions:

  • Osteopetrosis severe neonatal or infantile forms (OPTB1, OPTB4, OPTB8)
  • Osteopetrosis (infantile form, with nervous system involvement)
  • Osteopetrosis (intermediate form, osteoclast-poor)
  • Osteopetrosis (infantile form, osteoclast-poor with immunoglobulin deficiency)
  • Osteopetrosis, intermediate form (OPTB6, OPTB7, OPTB2)
  • Osteopetrosis with renal tubular acidosis
  • Osteopetrosis, late-onset form (OPTB1, OPTB2)
  • Osteopetrosis with ectodermal dysplasia and immune defect
  • Osteopetrosis (moderate form with defective leukocyte adhesion)
  • Pyknodysostosis
  • Osteopoikilosis
  • Melorheostosis with osteopoikilosis
  • Osteopathia striata with cranial sclerosis
  • Melorheostosis
  • Dysosteosclerosis 

Other sclerosing bone disorders

These include the following conditions:

  • Craniometaphyseal dysplasias
  • Diaphyseal dysplasia Camurati-Engelmann
  • Ghosal hematodiaphyseal dysplasia
  • Hypertrophic osteoarthropathy
  • Pachydermoperiostosis
  • Oculo-dento-osseous dysplasias
  • Osteoectasia with hyperphosphatasia
  • Sclerosteosis
  • Endosteal hyperostosis (van Buchem type)
  • Trichodento-osseous dysplasia
  • Diaphyseal medullary stenosis with malignant fibrous histiocytoma
  • Craniodiaphyseal dysplasia
  • Craniometadiaphyseal dysplasia (Wormian bone type)
  • Endosteal sclerosis with cerebellar hypoplasia
  • Lenz-Majewski hyperostotic dysplasia
  • Metaphyseal dysplasia (Braun Tinschert type)
  • Pyle disease

Osteogenesis imperfecta and decreased bone density group

This includes the following conditions:

  • Osteogenesis imperfecta (types 1, 2, 3, 4, and 5)
  • X-linked osteoporosis
  • Bruck syndrome (types 1 and 2)
  • Osteoporosis-pseudoglioma syndrome
  • LRP5 primary osteoporosis
  • Calvarial doughnut lesions with bone fragility
  • Idiopathic juvenile osteoporosis
  • Cole-Carpenter dysplasia
  • Spondylo-ocular dysplasia
  • Osteopenia with radiolucent lesions of the mandible
  • Ehlers-Danlos syndrome (progeroid form)
  • Geroderma osteodysplasticum
  • Cutis laxa (types 2A and 2B)
  • Singleton-Merten dysplasia

Abnormal mineralization group

This includes the following conditions:

  • Hypophosphatasias
  • Hypophosphatemic rickets
  • Neonatal hyperparathyroidism
  • Familial hypocalciuric hypercalcemia with transient neonatal hyperparathyroidism
  • Calcium pyrophosphate deposition disease

 Lysosomal storage diseases with skeletal involvement (dysostosis multiplex group)

These include the following conditions:

  • Mucopolysaccharidosis (Hurler; Hunter; Sanfilippo A, B, C, and D; Morquio A and B; Maroteaux-Lamy; and Sly)
  • Fucosidosis
  • Alpha mannosidosis
  • Beta mannosidosis
  • Aspartylglucosaminuria
  • GM1 gangliosidosis
  • Sialidosis
  • Sialic acid storage disease
  • Galactosialidosis
  • Multiple sulfatase deficiency
  • Mucolipidosis II and III

Osteolysis group

This includes the following conditions:

  • Familial expansile osteolysis
  • Mandibuloacral dysplasia types A and B
  • Progeria
  • Torg-Winchester syndrome
  • Hajdu-Cheney syndrome
  • Multicentric carpal-tarsal osteolysis with and without nephropathy 

Disorganized development of skeletal components group

This includes the following conditions:

  • Multiple cartilaginous exostoses 1, 2 and 3
  • Cherubism
  • Fibrous dysplasia, polyostotic form (McCune-Albright) [22]
  • Progressive osseous heteroplasia
  • Gnathodiaphyseal dysplasia
  • Metachondromatosis
  • Osteoglophonic dysplasia
  • Fibrodysplasia ossificans progressiva
  • Neurofibromatosis type 1
  • Carpotarsal osteochondromatosis
  • Cherubism with gingival fibromatosis
  • Dysplasia epiphysealis hemimelica
  • Lipomembraneous osteodystrophy with leukoencephalopathy
  • Enchondromatosis
  • Metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria
  • Genochondromatosis
  • Gorham-Stout disease

Overgrowth (tall stature) syndromes with skeletal involvement

These include the following conditions:

  • Weaver syndrome
  • Sotos syndrome
  • Sotos-like syndrome
  • Marshall-Smith syndrome
  • Proteus syndrome
  • CLOVES (congenital, lipomatous overgrowth; vascular malformations; epidermal nevi; scoliosis/skeletal/spinal anomalies) syndrome
  • Marfan syndrome
  • Congenital contractural arachnodactyly
  • Loeys-Dietz syndromes
  • Overgrowth syndrome with 2q37 translocations
  • Overgrowth with macrodactyly and NPR2 gain of function
  • Overgrowth syndrome with skeletal dysplasia

Genetic inflammatory/rheumatoid-like osteoarthropathies

These include the following conditions:

  • Progressive pseudorheumatoid dysplasia
  • Chronic infantile neurologic cutaneous articular syndrome
  • Sterile multifocal osteomyelitis, periostitis, and pustulosis
  • Chronic recurrent multifocal osteomyelitis with congenital dyserythropoietic anemia
  • Hyperostosis/hyperphosphatemia syndrome
  • Hyaline fibromatosis syndrome

Cleidocranial dysplasia and related disorders

These include the following conditions:

  • Cleidocranial dysplasia [23]
  • CDAGS (craniosynostosis and clavicular hypoplasia; delayed closure of the fontanel, cranial defects, and deafness; anal anomalies; genitourinary malformations; skin eruption) syndrome
  • Yunis-Varon dysplasia
  • Parietal foramina

Craniosynostosis syndromes and related disorders

These include the following conditions:

  • Pfeiffer syndrome
  • Apert syndrome
  • Craniosynostosis with cutis gyrata
  • Crouzon syndrome
  • Bent bone dysplasia
  • Crouzon-like craniosynostosis with acanthosis nigricans
  • Craniosynostosis (Muenke type)
  • Antley-Bixler syndrome
  • Craniosynostosis (Boston type)
  • Saethre-Chotzen syndrome
  • Shprintzen-Goldberg syndrome
  • Baller-Gerold syndrome
  • Carpenter syndrome
  • Coronal craniosynostosis
  • Complex craniosynostosis

Dysostoses with predominant craniofacial involvement

These include the following conditions:

  • Mandibulo-facial dysostosis (Treacher-Collins)
  • Oral-facial-digital syndrome type I
  • Weyers acrofacial (acrodental) dysostosis
  • Endocrine-cerebro-osteodysplasia
  • Craniofrontonasal syndrome
  • Frontonasal dysplasia types 1, 2, and 3
  • Hemifacial microsomia
  • Miller syndrome
  • Acrofacial dysostosis
  • Mandibulofacial dysostosis with microcephaly

Dysostoses with predominant vertebral with and without costal involvement

These include the following conditions:

  • Currarino triad
  • Spondylocostal dysostosis
  • Vertebral segmentation defect
  • Klippel Feil anomaly with laryngeal malformation
  • Cerebro-costo-mandibular syndrome
  • Cerebro-costo-mandibular-like syndrome with vertebral defects
  • Diaphanospondylodysostosis
  • Spondylo-megaepiphyseal-metaphyseal dysplasia

Patellar dysostoses

These include the following conditions:

  • Ischiopatellar dysplasia
  • Nail-patella syndrome
  • Genitopatellar syndrome
  • Ear-patella-short stature syndrome   

Brachydactylies (without extraskeletal manifestations)

These include the following conditions:

  • Brachydactyly (multiple types A-E)
  • Brachydactyly with anonychia

Brachydactylies (with extraskeletal manifestations)

These include the following conditions:

  • Brachydactyly-mental retardation syndrome
  • Hyperphosphatasia with mental retardation, brachytelephalangy, and distinct face
  • Brachydactyly-hypertension syndrome
  • Microcephaly-oculo-digito-esophageal-duodenal syndrome
  • Hand-foot-genital syndrome
  • Rubinstein-Taybi syndrome
  • Brachydactyly (Temtamy type)
  • Christian-type brachydactyly
  • Coffin-Siris syndrome1
  • Adams-Oliver
  • Catel-Manzke syndrome

Limb hypoplasia reduction defects group

This includes the following conditions:

  • Ulnar-mammary syndrome
  • de Lange syndrome
  • Fanconi anemia
  • Thrombocytopenia-absent radius
  • Thrombocythemia with distal limb defects
  • Holt-Oram syndrome
  • Okihiro syndrome
  • Cousin syndrome
  • Roberts syndrome
  • Split-hand-foot malformation with long bone deficiency
  • Tibial hemimelia
  • Tibial hemimelia-polysyndactyly-triphalangeal thumb
  • Acheiropodia
  • Tetra-amelia
  • Terminal transverse defect
  • Al-Awadi/Raas-Rothschild limb-pelvis hypoplasia-aplasia
  • Fuhrmann syndrome
  • RAPADILINO (radial ray defect, patellae hypoplasia or aplasia and cleft or highly arched palate, diarrhea and dislocated joints, little size and limb malformations, and long, slender nose and normal intelligence) syndrome
  • Poland syndrome
  • Femoral hypoplasia-unusual face syndrome
  • Femur-fibula-ulna syndrome
  • Hanhart syndrome
  • Gollop-Wolfgang
  • Scapulo-iliac dysplasia  

Ectrodactyly with and without other manifestations

This includes the following conditions:

  • Ankyloblepharon-ectodermal dysplasia-cleft lip/palate
  • Ectrodactyly-ectodermal dysplasia-cleft-palate syndromes
  • Ectrodactyly-ectodermal dysplasia-macular dystrophy syndrome
  • Limb-mammary syndrome
  • Split hand-foot malformation (isolated forms)
  • Hartsfield syndrome

Polydactyly-syndactyly-triphalangism group

This includes the following conditions:

  • Preaxial polydactyly (multiple types)
  • Postaxial polydactyly
  • Triphalangeal thumb
  • Greig cephalopolysyndactyly syndrome
  • Pallister-Hall syndrome
  • Synpolydactyly
  • Townes-Brocks syndrome
  • Lacrimo-auriculo-dento-digital syndromes
  • Acrocallosal syndrome
  • Acro-pectoral syndrome
  • Acro-pectoro-vertebral dysplasia
  • Mirror-image polydactyly of hands and feet
  • Cenani-Lenz syndactyly
  • Syndactyly, Malik-Percin type
  • Syndactyly of toes, telecanthus, ano- and renal malformations (STAR) syndrome
  • Syndactyly type Lueken
  • Oculodentodigital dysplasia
  • Syndactyly type 3
  • Syndactyly (Haas type)
  • Syndactyly with metacarpal and metatarsal fusion
  • Metacarpal 4-5 fusion syndrome
  • Syndactyly with craniosynostosis
  • Syndactyly with microcephaly and mental retardation
  • Meckel syndrome    

Defects in joint formation and synostoses

These include the following conditions:

  • Multiple synostoses syndrome type 3
  • Proximal symphalangism
  • Radio-ulnar synostosis with amegakaryocytic thrombocytopenia
  • Liebenberg syndrome
  • Congenital club foot
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