Skeletal Dysplasias

Diagnosis

Indications for Testing

  • Confirm diagnosis of a specific skeletal dysplasia to aid in prognosis and recurrence risk in the following
    • Pregnancies with ultrasound findings suggestive of a skeletal dysplasia in the fetus
    • Newborns or children suspected to be affected with a skeletal dysplasia
    • Pregnancies in which both parents are affected, and the fetus is at risk for homozygosity or compound heterozygosity
  • Determine the specific causative mutation(s) in affected adults prior to pregnancy

Laboratory Testing

  • Molecular genetic panels are available that evaluate for the most common skeletal dysplasias as well as those that are more rare

Clinical Background

Skeletal dysplasias, also known as osteochondrodysplasias, are a heterogeneous group of >350 disorders characterized by abnormal growth of cartilage or bone. Half of affected fetuses are stillborn or die within six weeks of birth. Some skeletal dysplasias are detected prenatally, while others are not detected until after birth or in later childhood. Only 40% of affected fetuses presenting prenatally are correctly identified by ultrasound alone.

The most common types of skeletal dysplasias detected prenatally include

  • Thanatophoric dysplasia
  • Osteogenesis imperfecta
  • Achondroplasia
  • Achondrogenesis types IB and II
  • Campomelic dysplasia
  • Diastrophic dysplasia

Epidemiology

  • Incidence – 1/5,000; however, most syndromes are rare

Clinical Presentation

  • Symptoms may include but are not limited to
    • Shortening of bones of the arms and legs >3 standard deviations below the mean
    • Head circumference >75th percentile
    • Bowed or fractured bones
    • Irregular, thickened, or thin bones
    • Undermineralization of the bones
    • Abnormal ribs and/or small chest circumference
    • Polydactyly
  • Skeletal dysplasia features

    Skeletal Dysplasia Features

    Gene

    Symbol

    Associated Skeletal Dysplasia(s)

    Inh*

    Physical Findings

    Lethality

    AGPS

    Rhizomelic chondrodysplasia punctata type 3

    AR

    Rhizomelia, cataracts, calcification in cartilage, growth retardation, severe ID**

    Most die in first decade

    ALPL

    Hypophosphatasia

    Perinatal/infantile forms AR; milder forms AD or AR

    Perinatal lethal form – respiratory insufficiency,hypercalcemia

    Infantile form – rickets

    Childhood form – low bone density and possible fractures

    Adult – loss of adult dentition, stress fractures

    Perinatal form may be lethal

    ARSE

    Chondrodysplasia punctata

    XLR

    Stippled epiphyses, brachytelephalangy, nasomaxillary hypoplasia, respiratory compromise, cervical spine stenosis, hearing loss, ID

    Most have normal life span

    COL1A1

    Osteogenesis imperfecta types I, II, III, IV

    AD

    Classic non-deforming (I) – blue sclera, normal stature, fractures but nondeforming

    Lethal (II) – blue sclera, fragile connective tissue, macrocephaly, deforming severe fractures

    Progressively deforming (III) – blue sclera, deforming fractures in newborn period

    Common variable (IV) – mild short stature, dental issues, adult-onset hearing loss, normal to grey sclera

    Type II is perinatally lethal; type III may be associated with neonatal death

    COL1A2

    Osteogenesis imperfecta types II, III, IV

    AR, AD

    COL2A1

    Achondrogenesis type 2; hypochondrogenesis; Czech dysplasia; Kniest dysplasia; Stickler syndrome; otospondylomegaepiphyseal dysplasia; platyspondylic skeletal dysplasia; spondyloepiphyseal dysplasia congenita; spondyloperipheral dysplasia

    AD

    Achondrogenesis type II – short limbs and phalanges, thoracic hypoplasia, hydropic fetal appearance

    Czech dysplasia – progressive pseudorheumatoid arthritis, platyspondyly, and short third and fourth toes

    Kniest dysplasia – joint contractures, cleft palate, myopia

    Achondrogenesis type II – neonatal lethality occurs

    COMP

    Pseudoachondroplasia (PSACH)

    AD

    Waddling gait with progressive short-limbed stature

    Most have normal life span

    CRTAP

    Osteogenesis imperfecta, types IIB and VII

    AR

    Type VII – rhizomelia, normal sclera

     

    DLL3

    Spondylocostal dysostosis

    AR

    Vertebral defects, rib abnormalities, scoliosis, pulmonary compromise

    Life span may be shortened due to respiratory complications

    DYNC2H1

    Short rib thoracic dystrophy 3 (with or without polydactyly)/asphyxiating thoracic dysplasia-3/Jeune syndrome

    AR

    Constricted thoracic cage, polydactyly variably present, cleft palate, major organ (eg, cardiac) defects

    Perinatal and neonatal lethality occurs

    EBP

    Chondrodysplasia punctata

    XLD

    Mild disease will have no symptoms; severe disease with multiple malformations and severe growth retardation in males

    Perinatal lethality can occur in males

    EVC

    Ellis-van Creveld syndrome

    AR

    Rhizomelia, short ribs, polydactyly, dysplastic nails, congenital heart defects

    May have normal lifespan

    EVC2

    Ellis-van Creveld syndrome 2; Weyers acrofacial dysostosis

    Ellis-van Creveld is AR; Weyers is AD

    Ellis-van Creveld syndrome 2 – rhizomelia, short ribs, polydactyly, dysplastic nails, congenital heart defects

    Weyers acrofacial dysostosis – dental anomalies, nail dystrophy, postaxial polydactyly, mild short stature

    May have normal lifespan

    FGFR1

    Osteoglophonic dysplasia

    AD

    Craniosynostosis, rhizomelia

    Most have normal life span

    FGFR2

    Bent bone dysplasia

    Most are AD; some are sporadic

    Craniosynostosis, facial anomalies, bent long bones

    Perinatal lethality

    FGFR3

    Achondroplasia; hypochondroplasia; thanatophoric dysplasia types I and II

    AD

    Achondroplasia – rhizomelia, frontal bossing, hypotonia, short ribs

    Hypochondroplasia – rhizomelia, joint laxity, macrocephaly, short broad bones

    Thanatophoric dysplasia – micromelia, narrow chest, bowed femurs, macrocephaly, cloverleaf skull

    Achondroplasia and hypochondroplasia –  most have normal life span

    Thanatophoric dysplasia – neonatal lethality

    FKBP10

    Osteogenesis imperfecta type XI/Bruck syndrome 1

    AR

    Osteogenesis imperfecta type XI – joint contractures, normal sclera; deforming fractures

    Bruck syndrome – bone fractures, clubfoot, normal to blue sclera, congenital joint contractures

    Shortened life span

    FLNA

    Frontometaphyseal dysplasia; terminal osseous dysplasia; otopalatodigital syndrome types I and 2, Melnick-Needles syndrome

    XLD

    Varying degrees of hypoplasia in bones; females may have manifestations of bone hypoplasia

    Most males die in first year of life

    FLNB

    Atelosteogenesis types I and III; Larsen syndrome; spondylo-carpal-tarsal synostosis syndrome

    AR

    Spondylocarpotarsal – short stature, scoliosis, clubfoot, hearing loss

    Larsen syndrome – congenital joint dislocations, club foot, scoliosis, cleft palate

    Atelosteogenesis types I and III – severe rhizomelia, dislocations

    Atelosteogenesis type I – perinatal lethality

    GNPAT

    Rhizomelic chondrodysplasia punctata type 2

    AR

    Rhizomelia, facial anomalies, congenital contractures, severe ID

    May have shortened life span

    HSPG2

    Dyssegmental dysplasia, Silverman-Handmaker type; Schwartz-Jampel syndrome type 1

    AR

    Dyssegmental dysplasia, Silverman-Handmaker type – rhizomelia, platyspondyly

    Neonatal lethality

    IFT80

    Asphyxiating thoracic dystrophy 2; short rib-polydactyly type 2

    AR

    Constricted thoracic cage, polydactyly variably present, cleft palate, major organ (eg, cardiac) defects

    Neonatal lethality occurs

    LBR

    Greenburg dysplasia

    AR

    Rhizomelia, short ribs, polydactyly, moth-eaten bones on x-ray

    Perinatal lethality

    LIFR

    Stuve-Wiedemann syndrome/Schwartz-Jampel syndrome type 2

    AR

    Bowed long bones, episodic hyperthermia, respiratory insufficiency

    Neonatal and early childhood lethality

    NEK1

    Short-rib thoracic dysplasia 6 with or without polydactyly/short rib-polydactyly syndrome type II (Majewski type)

    AR or digenic (NEK1/DYNC2H1)

    Constricted thoracic cage, polydactyly variably present, cleft palate, major organ (eg, cardiac) defects

                          

    Perinatal lethality common

    P3H1 (LEPRE1)

    Osteogenesis imperfecta, type VIII

    AR

    Severe deforming fractures, normal sclera, rhizomelia

    Neonatal lethality

    PEX7

    Rhizomelic chondrodysplasia punctata type 1

    AR

    Rhizomelia, punctate calcifications in bones, cataracts, growth retardation, ID

    May have childhood lethality

    POR

    Disordered steroidogenesis; Antley-Bixler syndrome

    AR

    Craniosynostosis, joint contractures, facial hypoplasia, impaired steroidogenesis

    Neonatal lethality common

    PPIB

    Osteogenesis imperfecta, type IX

    AR

    Severe deforming fracture, white sclera, rhizomelia

    Neonatal lethality

    RUNX2

    Metaphyseal dysplasia with maxillary hypoplasia with or without brachydactyly; cleidocranial dysplasia

    AD

    Cleidocranial dysplasia, dental anomalies, maxillary hypoplasia, vertebral malformation

    May have normal lifespan

    SERPINH1

    Osteogenesis imperfecta, type X

    AR

    Deforming fractures, dental problems, blue sclera

    May be associated with neonatal death

    SLC26A2

    Diastrophic dysplasia; achondrogenesis type Ib; atelosteogenesis type II

    AD

    Diastrophic dysplasia – rhizomelia, hitchhiker thumbs, large joint deformities, spinal deformities

    Achondrogenesis type Ib – short limbs and phalanges, thoracic hypoplasia, hydropic fetal appearance

    Atelosteogenesis type II – rhizomelia, hitchhiker thumbs, small chest, cleft palate, clubfoot, pulmonary hypoplasia

    Achondrogenesis type Ib – prenatal or newborn lethality

    Atelosteogenesis type II – newborn lethality

    Diastrophic dysplasia – may be newborn lethal, but most survive

    SLC35D1

    Schneckenbecken dysplasia

    AR

    Rhizomelia, vertebral abnormalities

    Neonatal lethality occurs

    SOX9

    Campomelic dysplasia

    AD

    Pierre Robin sequence, cleft palate, shortened bowed long bones, clubfoot

    Neonatal death possible; most have normal life span

    TRIP11

    Achondrogenesis type 1A

    AR

    Severe micromelia, thoracic hypoplasia, hydropic fetal appearance

    Prenatal or newborn lethality

    TRPV4

    Metatropic dysplasia; parastremmatic dwarfism; spondyloepiphyseal dysplasia (SED), Maroteaux type; spondylometaphyseal dysplasia, Kozlowski type; familial digital arthropathy-brachydactyly; autosomal dominant brachyolmia

    AD

    Metatropic dysplasia – brachydactyly, epimysial dysplasia, joint contracture, rhizomelia

    Parastremmatic dwarfism – joint contractures, rhizomelia, very short trunk

    SED, Maroteaux type – brachydactyly, rhizomelia, short trunk

    Spondylometaphyseal dysplasia, Kozlowski type – brachydactyly, short trunk rhizomelia 

    Familial digital arthropathy-brachydactyly – mild arthropathy

    Autosomal dominant brachyolmia – clinodactyly, mild short stature, no rhizomelia

    Metatropic dysplasia – may have prenatal or perinatal lethality

    TTC21B

    Short-rib thoracic dysplasia 4 with or without polydactyly

    AR

    Narrow thorax, rhizomelia, brachydactyly, ectodermal features, facial anomalies, endstage renal disease, growth retardation

    Childhood mortality from renal disease

    WDR19

    Cranioectodermal dysplasia 4/Sensenbrenner syndrome; short-rib thoracic dysplasia 5 with or without polydactyly/Jeune syndrome

    AR

    Narrow thorax, rhizomelia, brachydactyly, ectodermal features, facial anomalies, endstage renal disease, growth retardation

    Childhood mortality from renal disease

    WDR35

    Cranioectodermal dysplasia 2/Sensenbrenner syndrome; short rib thoracic dysplasia 7 with or without polydactyly

    AR

    Narrow thorax, rhizomelia, brachydactyly, ectodermal features, facial anomalies, endstage renal disease, growth retardation, developmental delay

    Childhood mortality from renal disease

    *Inh = inheritance; AD = autosomal dominant; AR = autosomal recessive; XLD = X-linked dominant; XLR = X-linked recessive; ID = intellectual disability

Indications for Laboratory Testing

  • Tests generally appear in the order most useful for common clinical situations
  • Click on number for test-specific information in the ARUP Laboratory Test Directory
Test Name and Number Recommended Use Limitations Follow Up
Skeletal Dysplasia Panel, Sequencing (39 Genes) and Deletion/Duplication (35 Genes), Fetal 2012010
Method: Massively Parallel Sequencing

Prenatal diagnosis for suspected fetal skeletal dysplasia

Clinical sensitivity – dependent on the specific skeletal dysplasia

Analytical sensitivity/specificity – 99%

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

 
Skeletal Dysplasia Panel, Sequencing (39 Genes) and Deletion/Duplication (35 Genes) 2012015
Method: Massively Parallel Sequencing/Exonic Oligonucleotide-based CGH Microarray

Preferred test for individuals with an undetermined skeletal dysplasia

Clinical sensitivity – dependent on the specific skeletal dysplasia

Analytical sensitivity/specificity – 99%

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

 
Skeletal Dysplasia Panel, Sequencing, 39 Genes 2012018
Method: Massively Parallel Sequencing

Acceptable test for individuals with an undetermined skeletal dysplasia

Clinical sensitivity – dependent on the specific skeletal dysplasia

Analytical sensitivity/specificity – 99%

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

 
Skeletal Dysplasia Panel, Deletion/Duplication, 35 Genes 2012007
Method: Exonic Oligonucleotide-based CGH Microarray

Preferred test for individuals with a previously identified familial deletion/duplication

Secondary diagnostic test if sequencing does not detect the causative mutation

Clinical sensitivity – dependent on the specific skeletal dysplasia

Analytical sensitivity/specificity – 99%

Deep intronic or regulatory region mutations and breakpoints for large deletions/duplications are not detected

Not all mutations in the tested genes are identified

Not all predisposing genes are interrogated

Diagnostic errors can occur due to rare sequence variations

 
Achondroplasia (FGFR3) 2 Mutations 0051266
Method: Polymerase Chain Reaction/Fluorescence Resonance Energy Transfer

Confirm clinical diagnosis of AP

Tests for c.1138G>A and c.1138G>C mutations

Clinical sensitivity 99%

Rare diagnostic errors may occur due to primer-site mutations

 
Achondroplasia (FGFR3) 2 Mutations, Fetal 0051265
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Establish DNA diagnosis in at-risk fetuses or those with consistent ultrasonographic features of AP

Tests for c.1138G>A and c.1138G>C mutations

Clinical sensitivity 99%

Rare diagnostic errors may occur due to primer-site mutations

 
Hypochondroplasia (FGFR3) 2 Mutations 0051367
Method: Polymerase Chain Reaction/Fluorescence Monitoring

Confirm clinical and/or radiological diagnosis of HP

Tests for c.1620C>A/G

Clinical sensitivity 70%

Rare diagnostic errors may occur due to primer-site mutations

 
Thanatophoric Dysplasia, Types 1 and 2 (FGFR3) 13 Mutations 0051506
Method: Polymerase Chain Reaction/Fragment Analysis

Confirm clinical diagnosis of TD1 or TD2

Tests for FGFR3 mutations c.742C>T (p.R248C), c.746C>G (p.S249C), c.1108G>T (p.G370C), c.1111A>T (p.S371C), c.1118A>G (p.Y373C), c.1948A>G (p.K650E), c.2419T>G (p. X807G), , c.2419T>A (p.X807R), c.2420G>C (p.X807S), c.2420G>T (p.X807L), c.2421A>T (p.X807C), c.2421A>C (p.X807C), and c.2421A>G (p.X807W)

Clinical sensitivity 99%

Rare diagnostic errors may occur due to primer-site mutations  
Thanatophoric Dysplasia, Types 1 and 2 (FGFR3) 13 Mutations, Fetal 0051508
Method: Polymerase Chain Reaction/Fragment Analysis

Confirm clinical diagnosis of TD1 or TD2

Tests for FGFR3 mutations c.742C>T (p.R248C), c.746C>G (p.S249C), c.1108G>T (p.G370C), c.1111A>T (p.S371C), c.1118A>G (p.Y373C), c.1948A>G (p.K650E), c.2419T>G (p. X807G), , c.2419T>A (p.X807R), c.2420G>C (p.X807S), c.2420G>T (p.X807L), c.2421A>T (p.X807C), c.2421A>C (p.X807C), and c.2421A>G (p.X807W)

Clinical sensitivity 99%

Specificity may be compromised by rare primer-site mutations