Skeletal Dysplasia

Until skeletal maturity, cartilage persists at the ends of bone in the growth plate, which is responsible for longitudinal bone growth. The cartilaginous template is eventually replaced by bone. Many of the genes mutated in skeletal dysplasias encode proteins that play critical roles in the growth plate. An understanding of the role in growth plate function gives important clues into the molecular pathology of the skeletal dysplasia and makes it easy to understand how a certain mutation causes a particular phenotype.[12] Examples of genes that play a role in growth plate chondrocytes and skeletal dysplasia include the following:

• Resting zone of the growth plate: SOX9 gene mutation causes camptomelic dysplasia, which is characterized by short and curved bone and is associated with sex reversal in which the female external genitalia does not match the male genotype. A heterozygous mutation is sufficient to cause the disease making this a dominant mutation, despite earlier reports suggesting that camptomelic dysplasia is a recessive disorder.

• Proliferation zone of the growth plate: FGFR3 gene mutation causes achondroplasia, hypochondroplasia, and thanatophoric dysplasia, despite the variability in severity.[13]

• Hypertrophic zone of the growth plate: PTHR1 gene mutation causes metaphyseal dysplasia. Activating mutations of the receptor causes the Jansen form, whereas inactivating mutations causes the Blomstrand form.[14, 15, 16, 17]

• Zone of terminal differentiation of the growth plate: RUNX2 gene mutation causes cleidocranial dysplasia.[18]

• Mutations in type II collagen cause a large number of disorders classified as spondyloepiphyseal dysplasia (ie, spondyloepiphyseal dysplasia congenita, Kniest dysplasia, Stickler syndrome, and achondrogenesis). Mutations in the smaller matrix components, such as type IX collagen and cartilage oligomeric protein, cause multiple epiphyseal dysplasia.

Frequency

United States

• Skeletal dysplasias represent approximately 5% of all congenital anomalies.

• The overall incidence of skeletal dysplasias is approximately 1 case per 4000-5000 births. The true incidence may be twice as high because many skeletal dysplasias do not manifest until short stature, joint symptoms, or other complications arise during childhood.

• Lethal skeletal dysplasias are estimated to occur in 0.95 per 10,000 deliveries.

• The 4 most common skeletal dysplasias are thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta, and achondrogenesis. Thanatophoric dysplasia and achondroplasia account for 62% of all lethal skeletal dysplasias.

• Achondroplasia is the most common nonlethal skeletal dysplasia.

Mortality/Morbidity

See the list below:

• Among infants with skeletal dysplasias detected at birth, approximately 13% are stillborn, and 44% die during the perinatal period.

• The overall frequency of skeletal dysplasias in infants who die perinatally is 9.1 per 1000.

Race

See the list below:

• No racial predilections are described.

Sex

See the list below:

• Males are primarily affected in X-linked recessive disorders. X-linked dominant disorders may be lethal in males.

• Otherwise, males and females are usually equally affected by skeletal dysplasias.

Age

See the list below:

• Skeletal dysplasias are usually detected in the newborn period or during infancy.

• Some disorders may not manifest until later in childhood.

The prognosis in skeletal dysplasias is variable. Some of these disorders are lethal in the neonatal period, while others present later in childhood with short stature.

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.

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 intellectual disability 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[19]

• 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

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:[20]

• 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:[21, 22]

• 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

  • 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)

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.

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) ^[23]
• 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) ^[24]
• 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 ^[25]
• 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-intellectual disability 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 intellectual disability
• 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

Diagnosis is based on family history and physical and radiographic findings, as well as genetic testing.

In general, clinical laboratory examinations in skeletal dysplasia are more helpful in patients with proportionate growth than in patients with disproportionate growth. Immune function, alkaline phosphatase, urinary phosphorylethanolamine, urinary mucopolysaccharides, lysosomal enzymes, and other assays may be indicated.

• Immune function studies

  • T-cell dysfunction–related susceptibility to severe varicella infection may be seen in cartilage-hair hypoplasia (metaphyseal dysplasia, McKusick type).

  • Neutropenia is a feature of Shwachman syndrome (metaphyseal dysplasia and pancreatic insufficiency).

  • Adenosine deaminase deficiency and severe combined immune deficiency may be present.

• Biochemical studies

  • Decreased serum alkaline phosphatase and increased urinary phosphorylethanolamine levels may indicate severe congenital hypophosphatasia.

  • Deficiency of a specific lysosomal enzyme may detect lysosomal storage disease.

  • An abnormal pattern of excretion of urinary glycosaminoglycan may indicate Kniest dysplasia (keratan sulfate), pseudoachondroplasia, and thanatophoric dysplasia.

Radiography

Conventional radiographic examination remains the most useful means of studying the dysplastic skeleton. The skeletal survey should include the skull (anteroposterior [AP], lateral views), chest (AP), spine (AP and lateral views including dedicated lateral view of the cervical spine), pelvis (AP), tubular bones (AP), and/or hands and feet (AP).[11]

Skull findings are as follows:

• Cranial sutures for evidence of craniosynostoses and presence of intersutural or Wormian bones in the lambdoid sutures

• Overall skull mineralization, thickness of the calvarium, and craniofacial proportions evaluated for evidence of frontal bossing, midface hypoplasia, mandibular hypoplasia, and retrognathia

• Shape of the sella turcica - Flattening of the anterior margin of the sella on the lateral view (J-shaped sella) can represent a normal variant or can be seen with space-occupying lesions of the sella or with certain dysplasias such as the mucopolysaccharidoses

Chest findings are as follows:

• Assessment of the number, shape (shortened, thickened, or gracile appearance), and morphology (fusions) of the ribs

• Scapular hypoplasia and clavicular absence or hypoplasia - This is seen with certain dysplasias, most notably with cleidocranial dysplasia; severe hypoplasia of the scapula is seen in camptomelic dysplasia and Antley-Bixler syndrome

• Cardiac silhouette and lungs evaluated for congenital heart disease seen with several syndromes and dysplasias, such as Holt-Oram syndrome and Ellis-van Creveld syndrome

• Rib shortening - Short-rib polydactyly syndromes, asphyxiating thoracic dysplasia, chondroectodermal dysplasia, metaphyseal dysplasia (associated with immune defect), and metatrophic dysplasia

Spine findings are as follows:

• AP view to evaluate right or left convex curvature (scoliosis)

• Lateral view to evaluate dorsal convex curvature (kyphosis or gibbus deformity) or accentuated lordotic curvature

• Cervical spine to evaluate ossification and shape of the dens for odontoid dysplasia and cervical instability, which may be observed in several dysplasias such as mucopolysaccharidoses, spondyloepiphyseal dysplasia congenita, pseudoachondroplasia, metatropic dysplasia, and diastrophic dysplasia[26, 27]

• Platyspondyly (flattening of the vertebral body) – (1) Without associated epiphyseal or metaphyseal abnormalities; (2) with associated epiphyseal or metaphyseal abnormalities (Severe platyspondylia may be observed in metatrophic dysplasia, lethal perinatal osteogenesis imperfecta, thanatophoric dysplasia, short-rib polydactyly syndromes, SED congenita, other types of SED, and Kniest dysplasia.)

• Coronal clefting (vertical lucency within the vertebral body on the lateral view) can be observed in Kniest, metatropic, and Desbuquois dysplasia)

• Narrowing of the interpediculate distance caudally on the AP view (suggests spinal stenosis), with a corollary finding of shortened pedicles on the lateral view, suggests achondroplasia and diastrophic dysplasia.

• Posterior scalloping of vertebral bodies, endplate irregularity, anterior beaking of vertebral bodies, anterior and posterior wedging of vertebral bodies, and tall vertebral bodies are also seen in the skeletal dysplasias

• Fusion and segmentation anomalies - More characteristic of syndromes such as Klippel-Feil or VACTERYL, as they are disorders of organogenesis

• Absence of calcification of vertebral bodies - Achondrogenesis types I and II

Pelvis findings are as follows:

• Absence or delay of ossification of the pubic bone in association with poor ossification of other parts of the skeleton in the neonate is seen in cleidocranial dysplasia

• Misshapen iliac bones and short and wide iliac bones with narrow sacrosciatic notches - Commonly seen in thanatophoric dysplasia, achondroplasia

• Abnormal pelvic configuration (small sacrosciatic notches) - Achondroplasia, Ellis-van Creveld syndrome, metatrophic dysplasia, thanatophoric dysplasia, and Jeune syndrome

• A flat or steep appearance or presence of marginal irregularity - Seen in Jeune syndrome

Extremity findings are as follows:

• Disproportional shortening should be evaluated for rhizomelia (relative shortening of the proximal extremities: humerus, femur), mesomelia (relative shortening of the middle portions of the extremities: radius, ulna, tibia, fibula), acromelia (relative shortening of the distal extremities), acromesomelia, and micromelia (generalized shortening of all extremities)

• Oval translucent area in proximal femora and humeri - Achondroplasia

• Dumbbell-shaped appearance of long bones - Kniest dysplasia and metatrophic dysplasia

• Bowing of limbs (camptomelia) - Camptomelic dysplasia, osteogenesis imperfecta syndromes, and thanatophoric dysplasia

• Calcified projections (spikes) at lateral femoral metaphyses - Thanatophoric dysplasia and achondrogenesis types I and II

• Cupping of the ends of the rib and long bones and metaphyseal flaring - Achondroplasia, metaphyseal dysplasias, asphyxiating thoracic dysplasia, and chondroectodermal dysplasia

• Long bone fractures - Osteogenesis imperfecta syndromes, hypophosphatasia, osteopetrosis, and achondrogenesis type I (Parenti-Fraccaro syndrome)

• Absence of epiphyseal ossification centers - SED congenita, multiple epiphyseal dysplasia, and other SED (unspecified)

• Cone-shaped epiphyses - Acrodysostosis, cleidocranial dysplasia, and trichorhinophalangeal dysplasia

• Proximal pointing of the metacarpals - dysostosis multiplex

• Stippling of the epiphyses - Chondrodysplasia punctata and other nonskeletal dysplasia syndromes, such as cerebrohepatorenal syndromes, warfarin-related embryopathy, chromosomal trisomy (trisomy 21, trisomy 18), lysosomal storage diseases (generalized gangliosidosis), phenytoin-induced embryopathy, Smith-Lemli-Opitz syndrome, anencephaly, cretinism, multiple epiphyseal dysplasia, SED, and normal variant hypoparathyroidism

• Polydactyly - Short rib polydactyly syndrome

• Duplicated calcaneus - Larsen syndrome

CT scan and MRI

CT scan and MRI of the skull and brain can reveal concurrent brain anomalies. Three-dimensional (3D) images can be used to evaluate craniofacial anomalies and deformities of the chondrocranium and cranial vault secondary to craniosynostosis and other skeletal dysplasias. These 3D architectural data are essential for reconstructive cosmetic surgery.

MRI of the spine is important to assess atlantoaxial instability seen in metatrophic skeletal dysplasia, Kniest dysplasia, certain mucopolysaccharidoses, multiple epiphyseal dysplasia, SED, cartilage-hair hypoplasia, and achondroplasia. Radiography, CT scan, and MRI findings can reveal stenosis of the foramen magnum and narrowing of the upper cervical spinal canal, which can produce severe hypotonia and spinal cord compression symptoms. MRI scans also can reveal edema and gliosis of the cervicomedullary cord secondary to the bony compression and other compression myelopathies resulting from progressive spinal deformities and scoliosis.

CT 3D reconstruction allows better surgical planning for osteotomies for complex pelvic and hip dysplasias.

Prenatal ultrasonography

Recently, noninvasive ultrasonography has gained acceptance in diagnosing fetal skeletal dysplasia. Prenatal diagnosis of skeletal diagnosis is usually made in women who previously delivered an infant with skeletal dysplasia or in whom findings of shortened, bowed, or anomalous extremities or other skeletal anomalies were depicted during routine prenatal ultrasonographic examination. For mothers who present with accurate gestational age, nomograms are available for assessing upper and lower limbs of the fetus. For mothers who present with uncertain gestational age, comparisons between limb dimensions and the head perimeter of the fetus can be used. Repeat ultrasonography examinations are usually required.

Prenatal diagnosis of skeletal dysplasia is often difficult, especially in the absence of family history. Currently, the technique used for the prenatal detection of these abnormalities is 2-dimensional (2D) ultrasonography,[28] which has a sensitivity of about 60%.[29]

Three-dimensional ultrasonography has been reported to have a somewhat better sensitivity compared with 2D ultrasonography and to be particularly useful for the evaluation of facial dysmorphism and anomalies involving the hands and feet.[30]

After 30 weeks’ gestation, standard orthogonal radiography of the maternal abdomen may help visualize the fetal skeleton and identify possible abnormalities in bone shape and size. However, superposition of fetal and maternal bones often makes it difficult to precisely visualize the fetal skeleton.[31]

Evaluation of long bones may be helpful. Measurements of all extremities can help detect predominant shortened segments, hypoplasia or absence of certain bones, degree of mineralization, bowing, angulation, and fractures or thickening secondary to callus formation.

Evaluation of short-limb dysplasia may reveal rhizomelic skeletal dysplasia (heterozygous achondroplasia, chondrodysplasia punctata), mild micromelic dysplasia (Jeune syndrome, Ellis-van Creveld syndrome, diastrophic dysplasia), mild bowed micromelic dysplasia (camptomelic dysplasia, osteogenesis imperfecta type III), or severe micromelic dysplasia (homozygous achondroplasia, thanatophoric dysplasia, osteogenesis imperfecta type II, achondrogenesis, congenital lethal form of hypophosphatasia, and short-rib polydactyly syndromes).

Evaluation of thoracic dimensions may reveal hypoplastic thorax, which is associated with severe or lethal skeletal dysplasias. This leads to pulmonary hypoplasia and is a frequent cause of death in patients with these conditions.

Evaluation of fetal ribs may reveal abnormal number which can be incidental or can be often associated with minor congenital anomalies and only occasionally with a severe malformation (Poland syndrome, VATER association, cleidocranial dysplasia, and camptomelic dysplasia, scoliosis, segmentation anomalies of the vertebrae, and abnormal karyotypes).

Evaluation of the fetal spine includes assessing the degree of ossification, hemivertebrae, scoliosis, gross vertebral disorganization, and platyspondylia.

Evaluation of hands and feet can reveal polydactyly, missing digits, and postural deformities including clubfoot and hypoplastic or hitchhiker thumbs.

Evaluation of fetal craniofacial structures can reveal defects of membranous ossification, orbits (evaluate to exclude ocular hypertelorism), retrognathia/micrognathia, facial or lip clefting, frontal bossing, and cloverleaf skull deformity.

Evaluation of fetal movement may be helpful. Movement is usually decreased in fetuses with bone dysplasias, especially lethal types.

Evaluation of associated anomalies includes maternal hydramnios, fetal hydrops, increased nuchal translucency thickness, and other fetal anomalies, such as congenital heart defects and cystic renal malformation.

The prenatal diagnosis of skeletal dysplasia is often initiated by the ultrasonographic findings in the mid trimester of a short femoral length, or by the knowledge of a previous familial history of skeletal dysplasia. Ultrasonography is highly specific for predicting lethal outcome, but of limited value for providing an accurate diagnosis of the bone disorder.

A study by Weaver et al indicated that in fetuses diagnosed with skeletal dysplasia, the risk of death from pulmonary hypoplasia can be predicted using the ratio of observed lung volume to expected lung volume (O/E lung volume) and the ratio of femur length to abdominal circumference (FL/AC). The study involved 23 pregnancies, in which magnetic resonance imaging (MRI) had been performed and ultrasonographic biometry data had been acquired. The results suggested that cutoff points for the O/E lung volume and FL/AC of 47.9% and 0.124, respectively, could be useful in predicting the lethality of pulmonary hypoplasia.[32]

Another study, by Nelson et al, indicated that in fetuses with skeletal dysplasia, the presence of the lethal form of the condition can be predicted in those with both hydramnios and an FL/AC ratio of less than 0.16. The study involved 45 fetuses with suspected skeletal dysplasia.[33]

Typical prenatal ultrasonographic features of skeletal dysplasias[34]

Thanatophoric dysplasia can indicate the following:

• Polyhydramnios

• Thickened soft tissues

• Micromelia

• Extremities at 90° to trunk

• Bowed femur (telephone receiver)

• Platyspondyly

• Frontal bossing, depressed nasal bridge

• Cloverleaf skull (type II)

Achondrogenesis can indicate the following:

• Polyhydramnios

• Thickened soft tissues

• Micromelia

• Absent ossification of vertebral bodies

• Normal calvarial ossification (type II)

• Small thorax, some with rib fractures (type IA)

Osteogenesis imperfecta IIA can indicate the following:

• Asymmetric micromelia

• Irregular/thickened bones

• Angulated bones

• Beaded ribs, small thorax

• Poorly ossified skull

Osteogenesis imperfecta IIB can indicate the following:

• Lower extremities more affected

• Less beading of ribs

• Poorly ossified skeleton

Osteogenesis imperfecta IIC can indicate the following:

• Thin bones, multiple fractures

• Thin beaded ribs

• Poorly ossified skull

Achondroplasia can indicate the following:

• Rhizomelia, mild mesomelia

• Stubby fingers

• Frontal bossing

• Narrowed interpediculate distance

Common abnormal prenatal ultrasonographic findings and differential diagnoses of skeletal dysplasias[35]

Poor mineralization of the calvaria can indicate the following:

• Achondrogenesis IA

• Cleidocranial dysplasia

• Hypophosphatasia

• Osteogenesis imperfecta II

Fractures of long bones (particularly femora) can indicate the following:

• Hypophosphatasia

• Neurofibromatosis

• Osteogenesis imperfecta II and III

Bent/bowed bones by ultrasound can indicate the following:

• Achondrogenesis I and II

• Antley-Bixler syndrome

• Atelosteogenesis I, II, and III

• Campomelic dysplasia

• Diastrophic dysplasia

• Hypophosphatasia

• Osteogenesis II and III

• Short-rib polydactyly syndrome I, II, III, and IV

• Stuve-Wiedemann syndrome

• Thanatophoric dysplasia I and II

Poor mineralization of the vertebrae can indicate the following:

• Achondrogenesis IA, IB, and II

• Atelosteogenesis I

Antenatal radiography has been used selectively when ultrasonography examinations cannot help establish a diagnosis or treatment plan adequately. Fetal radiography is especially helpful in obtaining more information about bone shape and mineralization, as well as confirming the diagnosis obtained by ultrasonography, particularly when termination of pregnancy is considered.

A babygram (AP and lateral views of an entire neonate to detect developmental anomalies of the entire skeletal system) should be performed on any infant with possible skeletal dysplasia because skeletal findings can provide essential diagnostic information needed for further genetic counseling. In addition, a babygram obtains information when consent for autopsy has been denied.

Amniography is used only occasionally to delineate fetal limbs.

Fetoscopy may be indicated in selected patients to allow direct depiction of structural defects such as limb shortening, polydactyly, facial cleft, or skin lesions.

Three-dimensional CT scanning is more precise in depicting the morphology of the spine (vertebral body shape) and pelvic bones, and in detecting bone synostosis. These abnormalities are often inconspicuous on ultrasonography but may be of great importance in establishing a precise diagnosis. However, 3-dimensional CT scanning is currently not sufficiently accurate for the analysis of metaphyseal deformities and for the assessment of bone density.[31]

Genetic testing plays a critical role in the diagnosis and management of skeletal dysplasias. Molecular diagnostic techniques have led to the identification of the underlying gene disorders in about two thirds of known skeletal dysplasias. Some of the more common include:

• FGFR3 (fibroblast growth factor 3)mutations - These lead to multiple disorders, with a range of severities, from achondroplasia and hypochondroplasia to thanatophoric dysplasias

• Collagen (COL1A1 and COL1A2) gene mutations - A major cause of osteogenesis imperfecta

• Mutational analysis of SOX9 in patients with camptomelic dysplasia and Antley-Bixler syndrome

The most appropriate genetic test should be determined based on clinical suspicion and in collaboration with a pediatric geneticist.

Other useful tests include sleep studies, which should be performed if a history of sleep apnea is noted.

Histopathologic and electron microscopic examinations of chondro-osseous tissue may be helpful in delineating a particular skeletal dysplasia.

• Histologic studies of growth plates

  • Cytoplasmic inclusions in resting chondrocytes reveal type I achondrogenesis, Kniest dysplasia, pseudoachondroplastic SED, type III short-rib polydactyly syndrome, and SED congenita.

  • Large ballooned chondrocytes with clear cytoplasm and markedly deficient cartilaginous matrix reveal type II achondrogenesis.

  • Resting cartilage with myxoid degeneration (Swiss cheese cartilage) may indicate Kniest dysplasia.

See the list below:

• Prenatal detection of skeletal dysplasias may influence the obstetric and perinatal treatment of affected infants. For example, a fetus with achondroplasia should undergo cesarean delivery to minimize the risk of possible CNS complications from vaginal delivery because of the cephalopelvic disproportion caused by a large fetal head and instability of the C1-C2 level of the fetal spine.

• Treatment is supportive. Medical care for individuals with skeletal dysplasia should be directed at preventing neurologic and orthopedic complications due to spinal cord compression, joint instability, and long bone deformity.

• Administer neonatal resuscitation and ventilatory support. Most infants with lethal skeletal dysplasias are stillborn or die within hours of birth. Given respiratory support, some infants with severe respiratory distress (eg, asphyxiating thoracic dysplasia) may survive.

• Obstructive sleep apnea may be treated by adenotonsillectomy, weight reduction, continuous airway pressure by a nasal mask, and tracheostomy in extreme cases.

• Monitoring height, weight, and head circumference of a child with skeletal dysplasia is important. Specific growth charts are available for specific conditions such as achondroplasia. Care should be taken to avoid obesity.

• Recombinant human growth hormone treatment has been tried in some patients with skeletal dysplasia. Growth hormone is not a logical treatment for the short stature associated with skeletal dysplasia because the defect is caused by abnormal bone growth in response to the stimulus growth hormone secreted at normal levels. Short-term treatment in patients with achondroplasia and hypochondroplasia has demonstrated an increase in growth velocity, which has been sustained for as many as 4-6 years. More trials are needed to confirm any long-term beneficial effects.

Surgical intervention depends on the signs and symptoms of skeletal dysplasia as follows:

• Thoracolumbar kyphosis can be controlled with a Milwaukee brace fitted with kyphosis pads to prevent progression to thoracic kyphosis.

• Progressive kyphosis, which may lead to spinal cord compression and spastic paraparesis, is best treated by anterior and posterior fusion. Lumbar lordosis with spinal stenosis responds to extensive lumbar laminectomy. Surgical decompression is required to relieve edema of the cervicomedullary cord secondary to bony compression.

• Progressive scoliosis requires spinal fusion.

• Ilizarov procedure, a bone-lengthening procedure, is an osteogenetic distractive osteotomy performed to mechanically induce diaphyseal bone growth. The procedure can lengthen limbs; rotate, angulate, and straighten bowed or deformed long bones; and offer reparative hope in some specific situations. Although recent experience has been more favorable (lower incidence of pain, infections, and neurologic/vascular compromise), postponement of such surgical intervention is advocated until the young person is able to make an informed decision.

• Bone marrow transplantation may benefit patients with skeletal dysplasia associated with congenital immune deficiencies, mucopolysaccharidosis, lipidosis, osteopetrosis, and Gaucher disease.

• Cesarean delivery must be performed in mothers with certain skeletal dysplasias (eg, achondroplasia) because of a small pelvis (cephalopelvic disproportion secondary to marked pelvic contracture). In achondroplasia, general anesthesia should be considered because the mother can be expected to have spinal stenosis, with the consequent risk associated with spinal or epidural anesthesia.

See the list below:

• Clinical geneticist

• Orthopedist

• Radiologist

• Pediatric surgeon

• Ophthalmologist

• Otolaryngologist

• Neurologist

• Physical and occupational therapists

See the list below:

• No special diet is required.

See the list below:

• For nonlethal skeletal dysplasias, physical activity may be limited because of existing orthopedic problems.

Guidelines for the management of children with achondroplasia are available from the American Academy of Pediatrics.[10]  The guidelines deal with examination and anticipatory guidance for patients from birth to early adulthood. They include the following for patients from birth to age 1 month:

• Confirm the diagnosis by radiographic studies
• Document measurements, including occipital-frontal circumference (OFC), body length, and body weight; plot these measurements on achondroplasia-specific growth charts; review the phenotype with the parents and discuss the specific findings with both parents whenever possible
• Measure the OFC at every pediatric contact during the first year
• Discuss the specific findings of achondroplasia with the parents (eg, that most individuals with achondroplasia have normal intelligence and life expectancy, that only 5-10% of infants with achondroplasia experience serious problems during infancy, and that growth hormones or other drug therapies or food or vitamin supplements do not significantly increase stature)
• If severe problems are found (eg, profound hypotonia or sustained ankle clonus, markedly diminished foramen magnum size compared with the achondroplasia standard, substantial deformation of the upper cervical spinal cord, hypoxemic episodes with minimal oxygen saturations below 85%), referral to a neurosurgeon or other physician skilled and experienced in the care and treatment of neurologic problems in children with achondroplasia should be initiated
• If the OFC is large or crosses percentiles on the achondroplasia-specific head-circumference chart, it is appropriate to refer the infant to a pediatric neurologist or pediatric neurosurgeon (although hydrocephalus is a lifelong risk, it is most likely to occur during the first 2 years)
• If there are signs of respiratory distress or evidence of poor weight gain despite adequate caloric intake, pulse oximetry (during feeding, when crying, and at rest) should be considered to monitor oxygenation
• Because most infants with achondroplasia develop a thoracolumbar kyphosis, parents should be counseled to avoid unsupported sitting and to avoid devices that cause curved sitting or “C sitting,” such as “umbrella-style” strollers and soft canvas seats during the first year of life; use of feeder seats for upright positioning should be recommended
• If severe kyphosis appears to be developing, consider a pediatric orthopedic surgical assessment to determine if bracing is needed
• Because severe thoracolumbar kyphosis is one mechanism that can give rise to spinal stenosis, unsupported sitting before there is adequate trunk muscle strength is discouraged
• Discuss the potential psychosocial implications that the child's disproportional short stature has for both the child and his or her parents
• Physicians should also refer the child or parents to a support group or other sources of support, provide educational books and pamphlets to the parents, discuss functional problems faced by individuals with achondroplasia, and review the prenatal diagnosis and recurrence risks for subsequent pregnancies

Japanese guidelines regarding the clinical management of achondroplasia, by Kubota et al, include the following recommendations[36] :

• It is recommended that cranial magnetic resonance imaging (MRI) be used to identify spinal cord compression resulting from foramen magnum stenosis
• It is recommended that foramen magnum decompression be carried out in cases of spinal cord compression resulting from foramen magnum stenosis associated with neurologic symptoms, abnormal neurological findings, and central respiratory disorders
• It is recommended that ventricular enlargement with neurologic symptoms (hydrocephalus) be identified via cranial MRI
• It is recommended that ventricular enlargement associated with neurologic symptoms (hydrocephalus) be managed with shunt surgery
• Management of obstructive sleep apnea through noninvasive positive pressure ventilation is suggested
• It is suggested that when obstructive sleep apnea exists in the presence of tonsillar/adenoid hypertrophy, surgical treatment be carried out
• It is recommended that spinal canal stenosis associated with neurologic symptoms be managed through surgical decompression
• It is suggested that after age 12 years and with informed assent, leg lengthening should be possible

 

Children with skeletal dysplasia should be followed by a multidisciplinary team composed of pediatricians, geneticists, and endocrinologists, as well as surgical subspecialists, including in otolaryngology, orthopedics, and neurosurgery.

Multiple family support organizations exist and are a good resource for families. These organizations include the following (see Patient Education for additional information):

• Little People of America
• Osteogenesis Imperfecta Foundation

Assistance with research and diagnosis is available from various organizations. The International Skeletal Dysplasia Registry, a research registry, is located at the University of California, Los Angeles.

See the list below:

• Intrauterine complications: Polyhydramnios and fetal hydrops are typically seen in patients with lethal types of chondrodystrophy, such as achondrogenesis or thanatophoric dysplasia. Occasionally, polyhydramnios may be seen in patients with nonlethal types of chondrodystrophy, such as achondroplasia.

• Respiratory complications: Respiratory distress secondary to small chest, small lungs, small or collapsing trachea, or small upper airway is seen in patients with many types of chondrodystrophy, such as asphyxiating thoracic dystrophy. Infants may snore, may have upper airway obstruction, or may experience hypoxic episodes.

• CNS complications: Hydrocephalus can occur in several types of skeletal dysplasia, notably in achondroplasia, metatropic dysplasia, and other conditions that affect the base of the skull, resulting in small foramen magnum and jugular foramen.

• Skeletal complications: Instability of the C1-C2 cervical spine that leads to spinal cord compression or nerve damage may be observed in patients with several types of chondrodystrophy, such as achondroplasia, SED congenita, and Morquio syndrome. Vertebral abnormalities, hip dysplasia, tight and loose joints, osteoarthritis, bowed legs, and fractures may vary.

• Muscular complications: Truncal hypotonia may lead to kyphoscoliosis in infants with achondroplasia or mucopolysaccharidoses. Thoracolumbar kyphosis may revert to marked lordosis in achondroplasia.

• Otolaryngologic complications: Progressive deafness is associated with repeated middle ear infections in patients with diastrophic dysplasia and achondroplasia. Hearing loss can be conductive or neurosensory in origin.

• Ophthalmologic complications: Myopia may predispose the patient to retinal detachment in Kniest dysplasia and SED congenita.

• Dental complications: Malocclusions, dental crowding, and structural abnormalities of teeth may be present in patients with many types of chondrodystrophy.

• Nutritional complications: Obesity is often a problem in patients with some types of chondrodystrophy, especially achondroplasia.

• Other complications

  • Anesthesia can be a problem in patients with some chondrodysplasias.

  • Unstable cervical vertebrae should be excluded.

  • Malignant hyperthermia may occur during anesthesia in patients with some types of chondrodysplasia, such as osteogenesis imperfecta.

  • Numerous obstetric and gynecologic problems are common in women with disproportionately short stature. Cesarean delivery of a baby may be required because of a contracted pelvis in the mother.

Although certain skeletal dysplasias are lethal in the newborn or infancy periods, patients with other types of skeletal dysplasia have normal or near-normal life expectancy. For patients with nonlethal skeletal dysplasias, prognosis depends on the degree of skeletal abnormalities and concomitant anomalies.

• Some patients may have difficulty finding a marital partner.

• Men with skeletal dysplasia complain less often of psychiatric symptoms and feel less stigmatized than do women.

• Medical and social aspects of the life course for adults with a skeletal dysplasia include the following:[37]

  • Overall, strong evidence suggests some barriers to equal opportunity in education and employment, and these, together with increased social isolation, are highly likely to exert a strong influence on financial situation and, therefore, on quality of life. All persons with skeletal dysplasia are physically impaired by virtue of the dysplasia. Only those with severe physical abnormalities are hampered in obtaining education and employment.

  • A substantial gap is observed in knowledge of the medical and social experiences of adults with skeletal dysplasias.

  • The relevance of the disability label is an important issue to many people with disabling conditions. It may be necessary to "come out" as disabled in order to qualify for support such as Disability Living Allowance (DLA).

  • Only by adopting a more stringent methodological approach to future research will it be possible to provide the robust evidence-base needed to inform future health and social service provision, as well as offering material for education and training purposes.

The birth of a child with a skeletal dysplasia is an emotionally difficult experience for parents. The term "dwarf" has especially negative connotations; thus, skeletal dysplasia is the preferred term for discussing these disorders. Up-to-date information and resources pertaining to skeletal dysplasia should be made available to families. The following resources may help parents meet other parents of children with skeletal dysplasia who can offer support and realistic appraisal of the implications:

• Little People of America (LPA), Inc

  • email: info@lpaonline.org

• Human Growth Foundation

  • email: hgf1@hgfound.org

• The MAGIC Foundation

  • email: mary@magicfoundation.org

• National Organization for Rare Disorders

  • email: orphan@rarediseases.org