NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2019.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Type II Collagen Disorders Overview

, MD and , MBBS, MD, FRACP, ARCPA (Hon).

Author Information

Initial Posting: .

Estimated reading time: 24 minutes

Summary

The purpose of this overview is to increase the awareness of clinicians regarding type II collagen disorders and their management.

The following are the goals of this overview.

Goal 1.

Describe the clinical characteristics of type II collagen disorders.

Goal 2.

Provide an evaluation strategy to identify the genetic cause of a type II collagen disorder in a proband.

Goal 3.

Inform genetic counseling of family members of an individual with a type II collagen disorder.

Goal 4.

Review management of type II collagen disorders.

1. Clinical Characteristics of Type II Collagen Disorders

Clinical Description

Type II collagen is an essential component of the cartilage extracellular matrix, and of major importance in endochondral bone formation, growth, and normal joint function. It is also necessary for normal development and function of the eye and the inner ear. Type II collagen disorders encompass a diverse group of clinical phenotypes characterized by skeletal dysplasia, ocular manifestations (e.g., cataract, myopia, subluxation of the lens, vitreous abnormalities, retinal detachment), hearing impairment, and orofacial features [Nishimura et al 2005, Kannu et al 2012, Spranger et al 2012a, Terhal et al 2015, Savarirayan et al 2019].

The spectrum of severity ranges from severe perinatal lethal disorders to milder conditions presenting in adulthood, with premature arthrosis as the primary feature. Included in this overview are the following specific type II collagen phenotypes (disorders included in the Nosology and Classification of Genetic Skeletal Disorders: 2015 Revision) [Bonafe et al 2015], which can be grouped according to severity.

Most severe (often lethal perinatally)

  • Achondrogenesis type II
  • Hypochondrogenesis
  • Platyspondylic dysplasia, Torrance type

Severe/moderately severe (neonatal presentation)

  • Kniest dysplasia
  • Spondyloepiphyseal dysplasia congenita (SEDC)
  • Spondyloepimetaphyseal dysplasia (SEMD), Strudwick type

Intermediate (neonatal/childhood/adolescent presentation)

  • Spondyloperipheral dysplasia
  • Spondyloepiphyseal dysplasia with metatarsal shortening
  • Stickler syndrome type 1

Mild (adolescent/adult presentation). Mild spondyloepiphyseal dysplasia (SED) with premature arthrosis

Phenotypes

Considerable phenotypic overlap notwithstanding, discriminating features can aid in the specific diagnosis (see Table 1). The following individual phenotypes are recognized.

Achondrogenesis type II is the most severe type II collagen disorder. Achondrogenesis type II usually presents in the prenatal setting with short stature, extremely short limbs (micromelia), narrow chest with pulmonary hypoplasia, extraskeletal features (e.g., flat midface, Pierre Robin sequence [PRS]), and edema/hydropic appearance. Radiographic findings include poor ossification of the axial skeleton, absent or delayed ossification of the vertebral bodies, absent ossification of the sacrum, and absent or severely delayed ossification of pubic and ischial bones. Iliac bones are small with crescent-shaped inner and inferior margins. The distal femora and proximal tibiae show delayed ossification, and the ribs and tubular bones are short. The majority of these infants do not survive to term, and are often delivered prematurely, are stillborn, or die shortly after birth due to cardiorespiratory failure [Spranger et al 2012b].

Hypochondrogenesis is characterized by short limbs, small thorax, flat facial profile, PRS, and delayed skeletal ossification, but with less severe clinical course and skeletal involvement than achondrogenesis type II. Vertebral bodies are small and ovoid, and unossified in the cervical region. The pubic bones are unossified and the ilia are hypoplastic. There is shortening of the long bones and delayed ossification in distal femoral and proximal tibial epiphyseal ossification centers. Infants with hypochondrogenesis have a short survival span ranging from days to months [Castori et al 2006].

Platyspondylic dysplasia, Torrance type is characterized by disproportionate short stature, short limbs, and coarse facial features. Skeletal findings consist of very thin vertebral bodies (severe platyspondyly), incomplete vertebral ossification, short ribs and narrow chest, short long bones with delayed/poor ossification, and splayed metaphyses of ribs and long bones. The majority of infants die at or shortly after birth; however, individuals with long-term survival have been reported [Nishimura et al 2004, Spranger et al 2012e].

Kniest dysplasia is a very severe type II collagen disorder, but results in live birth and longer survival. The clinical presentation is characterized by severe disproportionate short stature, short neck, short thorax, short extremities, and distinct ocular findings: myopia, vitreal abnormalities, and retinal detachment. Radiographically, Kniest dyplasia presents with pronounced abnormalities of bone modeling including platyspondyly with anterior wedging and coronal clefting of the lumbar vertebral bodies, delayed ossification in distal femoral and proximal tibial epiphyseal ossification centers, and short long bones with large metaphyses and epiphyses (dumbbell-type deformity of the long bones). Significant medical complications can occur mainly due to hypoplasia of dens leading to cervical instability and spinal cord compression, tracheolaryngomalacia and related respiratory complications, and early-onset arthrosis [Yazici et al 2010, Spranger et al 2012c, Sergouniotis et al 2015].

Spondyloepiphyseal dysplasia congenita (SEDC). Individuals with SEDC present neonatally with severe disproportionate short stature, short extremities (<5th percentile), characteristic facial features (hypertelorism, flat profile, PRS), myopia, and hearing loss. Radiographs display delayed/poor ossification of the vertebrae and the pubic bones, and the long bones are short with hypoplastic epiphyses. There is an increased risk for cervical instability and spinal cord compression (as seen in Kniest dysplasia), and individuals with SEDC are also at greater risk for tracheolaryngomalacia and related respiratory complications.

SEDC cannot be distinguished from SEMD, Strudwick type until later in the first year of life, since metaphyseal dysplasia in the latter is not present at birth [Spranger et al 2012d, Terhal et al 2015].

Spondyloepimetaphyseal dysplasia (SEMD), Strudwick type. Infants with SEMD, Strudwick type initially present with the same clinical and radiographic findings as those with SEDC. However, within the first year of life, metaphyseal flaring becomes evident, suggesting this diagnosis. The clinical course is similar to that of SEDC, with increased risk for cervical instability and spinal cord compression posing the greatest risk for these individuals [Walter et al 2007, Terhal et al 2015].

Spondyloperipheral dysplasia is characterized by mild-to-moderate disproportionate short stature and short extremities, brachydactyly type E, short ulnae, variable clubfeet, cleft palate, myopia, and hearing loss. Radiographs show ovoid vertebra, delayed ossification of pubic bones, and flattened and irregular epiphyses in the long bones in addition to the brachydactyly and short ulnae. Premature hip arthrosis causes joint pain [Zankl et al 2004].

Spondyloepiphyseal dysplasia (SED) with metatarsal shortening (formerly Czech dysplasia) is characterized by severe joint pain in the lower limbs before adolescence and shortening of the postaxial toes (usually the 3rd and/or 4th toes). Height is average and ocular and orofacial abnormalities are absent. Radiographs are characterized by mild platyspondyly with irregular endplates, narrowed intervertebral spaces, signs of osteoarthrosis including deformed femoral heads and dysplastic pelvis with irregular acetabulae, and shortening of the metatarsal and metacarpal bones [Kozlowski et al 2004, Marik et al 2004, Hoornaert et al 2007].

Stickler syndrome type 1 is one of the milder and more frequent type II collagen disorders [Barat-Houari et al 2016b, Barat-Houari et al 2016c], and the most common type of Stickler syndrome. It shows remarkable inter- and intrafamilial phenotypic variation, with severity ranging from involvement of many organs to milder phenotypes with only ocular manifestations and clinical and radiographic findings of early-onset osteoarthrosis. The ocular manifestations include high myopia, congenital membranous vitreous abnormalities (most often type 1 congenital vitreous anomaly or "membranous" vitreous phenotype), retinal detachment, and early-onset cataract. The orofacial abnormalities include flat facial profile (underdevelopment of the maxilla and nasal bridge), isolated small jaw, isolated cleft palate, or a combination (PRS), and hearing loss that can be conductive and/or sensorineural. The musculoskeletal manifestations include mild short stature or average stature, joint hypermobility, and skeletal dysplasia. Radiographic features include mild-to-moderate flattening of the vertebra with or without endplate irregularities, and irregular epiphyses of the long bones [Szymko-Bennett et al 2001, Liberfarb et al 2003, Rose et al 2005, Snead et al 2011, Acke et al 2012]. Typically, phenotypic findings present in childhood or later, although micrognathia, cleft palate, and polyhydramnios have been detected on prenatal ultrasound [Soulier et al 2002, Pacella et al 2010].

Mild spondyloepiphyseal dysplasia (SED) with premature-onset arthrosis is the mildest form of type II collagen disorder. It is characterized clinically by progressive joint pain and limitation of motion of the hip and knee joints, and radiographically by epiphyseal dysplasia and early-onset osteoarthrosis. The manifestations are age dependent, and height, vision, hearing, and orofacial structures are usually normal [Su et al 2008, Kannu et al 2010, Kannu et al 2011].

Table 1.

Clinical and Radiographic Features of Type II Collagen Disorders from Most to Least Severe

Type II Collagen
Disorder:
Most severe –
often perinatal lethal 1
Age of
Diagnosis
Poor/Delayed
Ossification
StatureExtraskeletal
Abnormalities
Distinguishing Feature(s) 2
ClinicalRadiographic
Achondrogenesis
type II
Prenatal++++++Extremely
short
  • Flat midface
  • PRS
  • Hydropic appearance
Often delivered prematurely, stillborn or die shortly after birth (hrs)
  • Absent or severely retarded ossification of vertebral bodies
  • Short ribs
  • Absent ossification of pubic bones, sacrum, ischial & iliac bones (small w/crescent-shaped inner & inferior margins)
  • Very short tubular bones w/delayed ossification in distal femoral & proximal tibial epiphyseal ossification centers
Hypochondro-
genesis
Prenatal+++++Extremely
short
  • Flat midface
  • PRS
Majority alive at birth, short survival (days to mos)
  • Poor/delayed ossification of axial skeleton
  • Very short tubular bones in the prenatal period
  • Short ribs
  • Vertebral bodies are small & ovoid, & unossified in cervical region.
  • Pubic bones are unossified.
  • Hypoplastic ilia
  • Short & relatively broad long bones w/delayed ossification in distal femoral & proximal tibial epiphysis
Platyspondylic
dysplasia,
Torrance type
Prenatal+++++Extremely
short
Coarse facial featuresMajority alive at birth, short survival (days to mos)
  • Platyspondyly
  • Incomplete vertebral ossification
  • Short ribs & narrow chest
  • Splayed metaphyses of ribs & long bones
Severe to moderately
severe – neonatal presentation
Age of
diagnosis
Poor/delayed
ossification
StatureExtraskeletal abnormalitiesDistinguishing feature(s) 2
ClinicalRadiographic
Kniest dysplasiaPerinatal++++Short
  • PRS
  • High prevalence of myopia, lens subluxation, retinal detachment, & other vitreal abnormalities
  • ↑ risk of tracheo-laryngomalacia
  • Most severe type II collagen disorder resulting in live birth
  • Long-term joint problems
  • Risk of cervical instability & myelopathy
  • Platyspondyly w/anterior wedging in low thoracic & lumbar region
  • Coronal cleft vertebral bodies
  • Delayed ossification in distal femoral & proximal tibial epiphyseal ossification centers
  • Dumbbell type deformity long bones (large metaphyses & epiphyses)
SEDCPerinatal+++Short
  • Flat facial profile, hypertelorism, PRS
  • Ocular abnormalities
  • ↑ risk of tracheo-laryngomalacia
  • Severe disproportionate short stature/extremities (˂5th %ile)
  • ↑ risk of cervical instability & spinal cord compression
  • Delayed/absent ossification of pubic bones, spine, & distal femoral & proximal tibial epiphyseal ossification centers
  • Delayed carpal & tarsal ossification
SEMD Strudwick typePerinatal+++Short
  • Flat facial profile, hypertelorism, PRS
  • Ocular abnormalities
  • ↑ risk of tracheo-laryngomalacia
  • Severe disproportionate short stature & short extremities (˂5th percentile)
  • ↑ risk of cervical instability & spinal cord compression
  • Delayed ossification of pubic bones, spine, & distal femoral & proximal tibial epiphyseal ossification centers
  • Metaphyseal dysplasia in 1st year of life (distinguishing SEMD, Strudwick type from SEDC)
Intermediate –
neonatal/child/
adult
Age of
diagnosis
Poor/delayed
ossification
StatureExtraskeletal abnormalitiesDistinguishing feature(s) 2
ClinicalRadiographic
Spondylo-
peripheral
dysplasia
Perinatal/
infancy
++Short
  • Myopia
  • Hearing loss
  • Moderate-to-mild disproportionate short stature
  • Short extremities
  • Brachydactyly
  • Occasionally clubfeet
  • Ovoid vertebra & irregular epiphyses in long bones
  • Brachydactyly type E
  • Short ulnae
SED with
metatarsal
shortening
Before
adolescence
NormalAverageUsually no extraskeletal abnormalities
  • Typical phenotypic hallmark: shortening of 3rd & 4th toes
  • Severe joint pain
  • Platyspondyly w/irregular endplates
  • Narrowed intervertebral spaces
  • Early osteoarthrosis in spine & lower limb joints (deformed femoral heads & dysplastic pelvis)
  • Metatarsal hypoplasia involving postaxial toes
Stickler type 1Variable
(typically
perinatal if
cleft palate)
NormalMild short
to average
  • High risk of high myopia, congenital membranous vitreous abnormalities, retinal detachment, & cataract
  • U-shaped cleft palate
  • Auditory manifestations
In case of PRS diagnosis most often in infancyRadiographic appearance of precocious or inflammatory arthritis (childhood)
Mild –
adolescent/
adult
Age of
diagnosis
Poor/delayed
ossification
StatureExtraskeletal abnormalitiesDistinguishing feature(s) 2
ClinicalRadiographic
Mild SED with premature-onset arthrosisAdolescence/
adult
NormalAverageVision, hearing, & orofacial structures are usually normal.Progressive joint pain & limitation of motion of the hip & knee jointEpiphyseal dysplasia & early-onset osteoarthrosis

PRS = Pierre Robin sequence; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenita; SEMD = spondyloepimetaphyseal dysplasia

1.

Can be very difficult to distinguish antenatally

2.

Features distinguishing this disorder from other type II collagen disorders

Genotype-Phenotype Correlations

There is currently no clear genotype-phenotype correlation in type II collagen disorders, and there is significant phenotypic overlap. However, data do support some general rules [Nishimura et al 2005, Hoornaert et al 2006, Terhal et al 2015, Barat-Houari et al 2016b, Barat-Houari et al 2016c, Leiden Open Variation Database (LOVD)]. Most pathogenic COL2A1 variants involve the triple helix domain.

  • Missense variants in the Gly position of the Gly-X-Y repeat motif cause substitution of glycine to a bulkier amino acid interfering with triple helix formation. This dominant-negative effect is generally seen in the more severe collagen type II disorders (e.g., achondrogenesis type II; hypochondrogenesis; platyspondyly, Torrance type; SEDC; and SEMD, Strudwick type).
  • In Kniest dysplasia exon skipping is more common [Barat-Houari et al 2016b, Barat-Houari et al 2016c], and it appears that splicing variants impose a higher risk for ophthalmologic complications and hearing loss [Terhal et al 2015].
  • Arginine-to-cysteine substitutions are most often associated with non-lethal phenotypes [Hoornaert et al 2006]. A p.Arg275Cys substitution in the Y position of the Gly-X-Y repeat motif causes SED with metatarsal shortening [Hoornaert et al 2007].
  • In Stickler syndrome type 1, nonsense and frameshift variants dominate, introducing a premature termination codon leading to haploinsufficiency [Richards et al 2006].

Penetrance

Penetrance in type II collagen disorders is high, if not complete; only rare cases of apparently reduced penetrance have been reported [Barat-Houari et al 2016b]. However, the milder disorders have age-dependent phenotypic manifestations, and wide inter- and intrafamilial phenotypic variation has been reported [Liberfarb et al 2003, Nakashima et al 2016]. At present, knowledge of underlying mechanisms is limited, but the phenotypic variation is likely caused by environmental factors and the polymorphisms in disease-modifying genes and/or regulatory elements [Bell et al 1997, Bi et al 1999, Liberfarb et al 2003, Kannu et al 2010, Nakashima et al 2016, Yasuda et al 2017].

Nomenclature

Achondrogenesis type II was formerly known as Langer-Saldino dysplasia.

Spondyloperipheral dysplasia is also referred to as spondyloperipheral dysplasia-short ulna syndrome.

Spondyloepiphyseal dysplasia with metatarsal shortening is also referred to as Czech dysplasia.

Prevalence

The exact prevalence of type II collagen disorders is not known. However, Stickler syndrome type 1 may be the most common type II collagen disorder; the overall incidence of all types of Stickler syndrome is estimated at 1/10,000 [Rose et al 2001].

Differential Diagnosis

The differential diagnosis of type II collagen disorders includes a range of disorders from severe, often lethal skeletal dysplasia with abnormal ossification and major skeletal abnormalities, to milder conditions with limited clinical and radiographic findings. Disorders with a known genetic etiology are listed (from most to least severe) in Table 2a; disorders of unknown or multifactorial etiology are listed in Table 2b.

Table 2a.

Disorders with Known Genetic Etiology to Consider in the Differential Diagnosis of Type II Collagen Disorders

Type II Collagen
Disorder
Differential Diagnosis DisorderGene(s)MOIClinical Features of Differential Diagnosis Disorder
Overlapping w/type II collagen disordersDistinguishing from type II collagen disorders
Most severe 1
achondrogenesis type II; hypochondrogenesis;
platyspondylic dysplasia, Torrance type
Severe OI (see COL1A1/2-OI)COL1A1
COL1A2
CRTAP
P3H1 (LEPRE1)
PPIB
AD
AR
  • Poor/delayed ossification
  • Short limbs
  • Multiple fractures & deformities of long bones
  • No extraskeletal type II collagen characteristic abnormalities 2
HypophosphatasiaALPLAD
AR
Poor/delayed ossification
  • Absent ossification of the skull
  • Absent ossification of posterior elements of vertebrae
  • Low serum ALP
  • No extraskeletal type II collagen characteristic abnormalities 2
Achondrogenesis type 1A
(OMIM 200600)
TRIP11AR
  • Poor/delayed ossification
  • Hydropic appearance
  • Poorly ossified skull bones
  • Short, thin, easily fractured ribs
  • Tubular bones more severely shortened & bowed
Achondrogenesis type 1BSLC26A2AR
  • Poor ossification
  • Flat face, short neck
  • Hydropic appearance
  • Crescent-shaped ilia
  • Extremely short limbs w/loss of longitudinal orientation
  • Short fingers & toes
  • Hypoplasia of thorax
  • Protuberant abdomen
Atelosteogenesis type 2SLC26A2AR
  • Often delayed ossification of upper thoracic vertebra & pubic bone
  • Short limbs
  • Cleft palate, distinctive facial features (midface retrusion, depressed nasal bridge, micrognathia)
  • Hitchhiker (abducted) thumbs
  • Poor/delayed ossification less severe than severe type II collagen disorder
  • Distal tapering of humeri
  • Hypoplastic fibulae
Diastrophic dysplasiaSLC26A2AR
  • Short limbs
  • Spine & joint deformities
Hitchhiker thumbs/toes
Dyssegmental dysplasia, Silverman-Handmaker type (OMIM 224410)
(may include Rolland-Desbuquois type)
HSPG2AR
  • Narrow chest
  • Short limbs
  • Cleft palate
  • Vertebral disorganization
  • Marked differences in size & shape of vertebral bodies (anisospondyly)
  • Bowed long bones
Severe to
moderately
severe
Kniest dysplasia; SEDC; SEMD, Strudwick type
Metatropic dysplasia
(see TRPV4-Associated Disorders
TRPV4AD
  • Limb shortening
  • Spine & joint deformities
  • Narrow transverse diameter of thorax
  • Vertebral bodies diamond/oval shape, no coronal clefts
  • Medially placed (inset) pedicles
  • More distal flaring in femur & proximal tibia
  • Most often no facial, ophthalmic, or auditory abnormalities 2
  • Normal ossification of skeleton
Intermediate
severity –
spondyloperipheral dysplasia; SED w/metatarsal shortening (Czech dysplasia); 3 Stickler syndrome type 1
MED, ADCOL9A1
COL9A2
COL9A3
COMP
MATN3
ADPresents in early childhood, usually w/pain in hips &/or knees
  • No facial, ophthalmic, or auditory abnormalities 2
  • Often no spine involvement
MED, recessiveSLC26A2AR
  • Presents in early childhood, usually w/pain in hips &/or knees
  • Brachydactyly
  • No facial, ophthalmic, or auditory abnormalities 2
  • Clubfeet
  • Cleft palate
  • Double-layered patella observed on lateral knee radiographs in 60%
  • Often no spine involvement
Progressive pseudorheumatoid dysplasia
(SED w/progressive arthropathy)
CCN6AR
  • Joint pain, multiple joint contractures, & prominent interphalangeal joints
  • Short stature
  • Moderate platysplondyly
  • Widening of the metaphyses, enlarged ephiphyses
  • Early osteoarthritis
  • No facial, ophthalmic, or auditory abnormalities 2
  • Toes are distinct from SED w/metatarsal shortening 3
Stickler syndrome types 2, 3, 4, & 5COL11A1
COL11A2
COL9A1
COL9A2
COL9A3
AD
AR
  • Craniofacial, ophthalmic, & auditory abnormalities
  • Skeletal manifestations on x-ray (spondyloepiphyseal dysplasia) & joint involvement
  • Ophthalmologic complications often less severe than Stickler type 1
  • Ocular phenotypes in other Stickler subtypes most often comprise type 2 congenital vitreous anomaly ("beaded" vitreous phenotype).

AD = autosomal dominant; ALP = alkaline phosphatase test; AR = autosomal recessive; OI = osteogenesis imperfecta; MED = multiple epiphyseal dysplasia; MOI = mode of inheritance; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenita; SEMD = spondyloepimetaphyseal dysplasia

1.

Can be very difficult to distinguish antenatally

2.

Comprising characteristic type II collagen ocular, auditory, and orofacial abnormalities (i.e., high myopia, retinal detachment, hearing impairment, Pierre Robin sequence)

3.

Shortening of the third and/or fourth toes is a classic distinguishing hallmark of SED with metatarsal shortening (Czech dysplasia).

Table 2b.

Disorders of Unknown Etiology to Consider in the Differential Diagnosis of Type II Collagen Disorders

Type II Collagen DisorderDifferential Diagnosis DisorderClinical Features of Differential Diagnosis Disorder
Overlapping w/type II collagen disordersDistinguishing from type II collagen disorders
Intermediate severity –
spondyloperipheral dysplasia; SED w/metatarsal shortening (Czech dysplasia) 1; Stickler syndrome type 1
Juvenile idiopathic arthritisPresents in childhood, usually w/joint painNo facial, ophthalmic, or auditory abnormalities 3
Calve-Legg Perthes 2Presents in childhood, usually w/hip pain
  • No facial, ophthalmic, or auditory abnormalities 3
  • Often unilateral, & if bilateral (10%-15% of cases) often asynchronous involvement (femoral heads in different stages of disease) 2
  • No spine involvement
Mild severity –
mild SED w/premature arthrosis
Rheumatoid arthritis
  • Joint pain
  • Radiographic skeletal changes of osteoarthritis
More pronounced clinical & laboratory signs of inflammation
Juvenile idiopathic arthritisJoint pain
  • No facial, ophthalmic, or auditory abnormalities 3
  • Often presents at younger age

AD = autosomal dominant; ALP = alkaline phosphatase test; AR = autosomal recessive; MED = multiple epiphyseal dysplasia; MOI = mode of inheritance; OI = osteogenesis imperfecta; SED = spondyloepiphyseal dysplasia; SEDC = spondyloepiphyseal dysplasia congenita; SEMD = spondyloepimetaphyseal dysplasia

1.

Shortening of the third and/or fourth toes is a classic distinguishing hallmark of spondyloepiphyseal dysplasia (SED) with metatarsal shortening (Czech dysplasia).

2.

COL2A1 pathogenic variants have been associated with a Calve-Legg-Perthes-like phenotype (more accurately dysplastic proximal femoral epiphyses). Bilateral hip involvement, especially symmetrical and synchronous, is suggestive of a type II collagen disorder. Bilateral involvement of femoral heads (including different stages of severity) warrant further attention and workup in general.

3.

Comprising characteristic type II collagen ocular, auditory, and orofacial abnormalities (i.e., high myopia, retinal detachment, hearing impairment, PRS)

2. Evaluation Strategies to Identify the Genetic Cause of a Type II Collagen Disorder in a Proband

A collagen type II disorder should be suspected in fetuses and individuals presenting with classic or suggestive clinical and radiologic findings of collagen type II dysfunction.

Establishing a specific genetic cause of a type II collagen disorder:

  • Can aid in discussions of prognosis (which are beyond the scope of this GeneReview) and genetic counseling;
  • Is based on clinical and radiologic findings and the identification of a pathogenic variant in COL2A1, and involves medical history, physical examination, x-rays, family history, and genetic testing.
    Note: As no formal clinical diagnostic criteria exist, specific diagnosis should be confirmed by genetic testing.

Medical history. A collagen type II disorder should be suspected in a fetus or individuals with classic disease hallmarks of short stature, skeletal dysplasia, ocular manifestations (early cataract, myopia, vitreous abnormalities, retinal detachment), small jaw, cleft palate (Pierre Robin sequence), flat midface, hearing impairment, joint hypermobility, and early-onset arthrosis (see Table 1).

Physical examination. A physical examination should include standard growth parameters (height, weight, head circumference) and address the following key issues: body proportions, craniofacial features (flat facial profile, widely spaced eyes, retrognathia, and cleft palate), spine, and joints (joint enlargement, hypermobility, contractures). Specific radiographic findings are associated with each type II collagen disorder (see Table 1).

Family history. A three-generation family history should be taken, with attention to relatives with clinical and radiographic manifestations of type II collagen disorders (e.g., specific questions about cleft palate, joint pain/deterioration, sudden visual loss / retinal detachment, hearing loss). Relevant findings from direct examination or review of medical records (including results of molecular genetic testing) must be documented.

Molecular genetic testing approaches can include single-gene testing and use of a multigene panel:

  • Single-gene testing. Sequence analysis of COL2A1 detects small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exon or whole-gene deletions/duplications are not detected. Perform sequence analysis first. If no pathogenic variant is found, perform gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications. Single-gene testing of COL2A1 can be considered if clinical findings and/or family history indicate that pathogenic variants in this particular gene are most likely (see Table 1).
  • A multigene panel that includes COL2A1 and other genes of interest (see Table 2a and Table 2b) should be considered, particularly in instances with diagnostic uncertainty (e.g., prenatal evaluations), to identify the genetic cause of the condition at the most reasonable time and cost while limiting identification of variants of uncertain significance and pathogenic variants in genes that do not explain the underlying phenotype. Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Multigene panels may include genes not associated with the condition discussed in this GeneReview. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused exome analysis that includes genes specified by the clinician. (4) Methods used in a panel may include sequence analysis, deletion/duplication analysis, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended.
    For an introduction to multigene panels, click here. More detailed information for clinicians ordering genetic tests can be found here.

3. Genetic Counseling

Mode of Inheritance

Type II collagen disorders are inherited in an autosomal dominant manner. However, rare cases of autosomal recessive inheritance in spondyloepiphyseal dysplasia congenita have been reported [Tham et al 2015, Barat-Houari et al 2016a].

Risk to Family Members

Autosomal Dominant Inheritance

Parents of a proband

  • Most individuals diagnosed with a severe form of type II collagen disorder have the disorder as the result of a de novo pathogenic variant. The overall proportion of cases caused by a COL2A1 de novo pathogenic variant is unknown.
  • Many individuals diagnosed with the milder form of type II collagen disorder have an affected parent. Clinical variability within a family can be extensive; however, severe and mild forms are not seen in family members with the same pathogenic variant (i.e., the specific type II collagen diagnosis appears to run true in a family, but with variable expressivity).
  • Recommendations for the parents of a proband with an apparent de novo pathogenic variant include molecular genetic testing and clinical examination (see Evaluation of Relatives at Risk).
  • If the pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, possible explanations include a de novo pathogenic variant in the proband and somatic and/or germline mosaicism in a parent. The incidence of somatic and germline mosaicism is unknown, but it is likely rare since only a few cases of genetically proven somatic and germline mosaicism have been reported in the literature [Nagendran et al 2012, Okamoto et al 2012, Stevenson et al 2012].
  • The family history of some individuals diagnosed with a milder form of type II collagen disorder may appear to be negative because of failure to recognize the disorder in mildly affected family members. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
  • Note: If the parent is the individual in whom the COL2A1 pathogenic variant first occurred, s/he may have somatic mosaicism for the variant and may be mildly/minimally affected.

Sibs of a proband. The risk to the sibs of the proband depends on the clinical/genetic status of the proband's parents:

Offspring of a proband. Each child of an individual with a type II collagen disorder has a 50% chance of inheriting the COL2A1 pathogenic variant.

Other family members. The risk to other family members depends on the status of the proband's parents: if a parent has the pathogenic variant, his or her family members may be at risk.

Autosomal Recessive Inheritance

Parents of a proband

Sibs of a proband

  • At conception, each sib of an affected individual has a 25% chance of inheriting two COL2A1 pathogenic variants (one from each heterozygous parent), a 50% chance of inheriting one COL2A1 pathogenic variant, and a 25% chance of inheriting a COL2A1 pathogenic variant from neither parent.
  • Heterozygous sibs are predicted to be either unaffected or mildly affected. Homozygous sibs will be affected in a manner similar to the affected individual but, because of variable expressivity, may have a more or less severe clinical outcome.

Offspring of a proband. Unless an individual with biallelic COL2A1 pathogenic variants has children with an individual who also has a type II collagen disorder, his/her offspring will be obligate heterozygotes for a pathogenic variant in COL2A1.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Considerations in families with an apparent de novo pathogenic variant. When neither parent of a proband with an autosomal dominant condition has the pathogenic variant identified in the proband or clinical evidence of the disorder, the proband may have a de novo pathogenic variant or a parent may have somatic and/or germline mosaicism for the pathogenic variant. However, non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing and Preimplantation Genetic Diagnosis

Once the COL2A1 pathogenic variant(s) have been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic diagnosis are possible.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. While most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

4. Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with type II collagen disorders, the evaluations summarized in Table 3 (if not performed as part of the evaluation that led to the diagnosis) are recommended:

Table 3.

Recommended Evaluations Following Initial Diagnosis in Individuals with Type II Collagen Disorders

System/ConcernEvaluationComment
SkeletonComplete radiographic survey if indicated
  • Often already performed in order to establish diagnosis
  • To asses extent of skeletal malformations
Cervical spine
  • Flexion-extension radiograph
  • Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young individuals w/delayed ossification in upper cervical spine)
Evaluate for cervical instability & risk of spinal cord compression.
Thoracolumbar spineClinical examination & radiographs where indicatedEvaluate for progressive scoliosis.
Respiratory
  • Pulmonary function tests
  • Polysomnography
  • To assess extent of respiratory insufficiency in severe presentations (PRS, small thorax, pulmonary hypoplasia)
  • To identify sleep apnea (central sleep apnea due to unrecognized unstable cervical spine, obstructive sleep apnea due to tracheobronchomalacia & cleft palate sequelae)
  • To identify respiratory insufficiency in those w/severe kyphoscoliosis
EyesDilated eye examinationPreferably by an expert ophthalmologist familiar w/the ophthalmic complications (e.g., high myopia, vitreous changes, retinal detachment, early cataract, vision problems, blindness)
ENT/Mouth
  • Hearing evaluation
  • Evaluation for cleft palate
FeedingSwallowing assessmentIn individuals w/PRS
Musculoskeletal
  • Clinical examination
  • Referral to orthopedic surgeon if indicated
  • Referral to physiotherapist if indicated
Functional testing / activities of daily living should be considered.
GeneticsConsultation w/clinical geneticist &/or genetic counselor
Psychosocial issues
  • Awareness
  • Referral to resources
Issues related to (e.g.) short stature, dysmorphic facial features, poor eyesight &/or hearing impairment, pain

PRS = Pierre Robin sequence

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with Type II Collagen Disorders

Manifestation/
Concern
TreatmentConsiderations/Other
Cervical spine instability w/spine compressionSurgical management for medullopathy (C1-C2 fixation)Management by an expert familiar w/rare skeletal dysplasia & spine involvement
ScoliosisSurgery for severe, progressive scoliosisIn young children, progressive scoliosis can be treated non-surgically (e.g., brace).
Respiratory insufficiency
  • Supported ventilation, CPAP
  • Surgery of cleft palate
Sleep apnea
  • Referral to pulmonologist & sleep medicine physician
  • Supported ventilation, CPAP, surgery of PRS
In case of central sleep apnea due to unrecognized unstable cervical spine, referral for evaluation & management
Cleft palateSurgery
High myopia, vitroretinal complications, & early cataract
  • Refractive errors should be corrected w/spectacles.
  • Individuals at risk should be informed about signs & symptoms of retinal detachment, & should be advised about immediate evaluation & treatment, when symptoms occur.
  • Management of vitreoretinal complications by an expert ophthalmologist familiar w/the ophthalmic complications.
  • Consider prophylactic retinopexy in Stickler syndrome type 1 (COL2A1-related)
Hearing impairmentHearing aids &/or surgery if indicated
Joint problems (laxity, contractures, pain due to early-onset arthrosis)
  • Referral to orthopedic surgeon for evaluation
  • Referral to physiotherapist
  • Referral to occupational therapist if indicated
  • Analgesics
  • Advice on joint-friendly activities (e.g., swimming, cycling)
  • Consider need for a mobility device.
  • Avoidance of physical activities that strain joints, when possible
Lower-limb malalignment
  • Guided growth surgery
  • Osteotomy
ObesityReferral to clinical nutritionistEven if weight is normal, importance of avoiding obesity should be emphasized.
Psychosocial problems
  • Referral to resources
  • Referral to psychologist

CPAP = continuous positive airway pressure

Surveillance

Table 5.

Recommended Surveillance for Individuals with Type II Collagen Disorders

System/
Concern
EvaluationFrequency
General healthPhysical examinationAnnually or as indicated
Cervical spine
  • Flexion-extension radiograph
  • Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Every 2-3 yrs in those w/severe type II collagen disorder & no instability
Thoracolumbar spine
  • Clinical examination
  • Radiographs when indicated
Every 6-12 mos, depending on severity
Respiratory
  • Pulmonary function tests
  • Polysomnography
On a regular basis in individuals w/severe type II collagen disorder or severe, progressive kyphoscoliosis
EyesDilated eye examination
  • Annually unless complications
  • Consider prophylactic retinopexy in Stickler syndrome type 1 (COL2A1-related)
ENT/
Mouth
  • Hearing evaluation
  • Evaluation for cleft palate & palatal insufficiency
Every 6-12 mos depending on severity
FeedingSwallowing assessmentOn a regular basis until normal feeding
Musculoskeletal
  • Clinical examination
  • Referral to orthopedic surgeon if indicated
  • Referral to physiotherapist if indicated
Annually or as indicated
ObesityWeightAnnually or as indicated
Psychosocial concernsSpecific attention to any issues when taking history & during physical examinationAnnually or as indicated

Agents/Circumstances to Avoid

In individuals with cervical spine instability, extreme neck extension and neck flexion and contact sports should be avoided.

In case of general anesthesia, the cervical spine should be assessed by imaging prior to the procedure [White et al 2017].

Evaluation of Relatives at Risk

It is appropriate to clarify the clinical/genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from regular surveillance in order to avoid/prevent common complications. Evaluations can include:

  • Molecular genetic testing if the pathogenic variant in the family is known;
  • Clinical examination, radiographs, eye examination, and hearing evaluation if the pathogenic variant in the family is not known.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

In individuals with a small pelvis, delivery by cesarean section should be considered. However, each individual should be assessed by an obstetrician familiar with skeletal dysplasia [Savarirayan et al 2018].

Therapies Under Investigation

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • My46 Trait Profile
  • National Library of Medicine Genetics Home Reference
  • National Library of Medicine Genetics Home Reference
  • Stickler Involved People (SIP)
    15 Angelina
    Augusta KS 67010
    Phone: 316-259-5194
    Email: sip@sticklers.org
  • Stickler Syndrome Support Group (SSSG)
    PO Box 3351
    Littlehampton West Sussex BN16 9GB
    United Kingdom
    Phone: 01903 785771
    Email: info@stickler.org.uk
  • Little People of America, Inc. (LPA)
    250 El Camino Real
    Suite 201
    Tustin CA 92780
    Phone: 888-572-2001 (toll-free); 714-368-3689
    Fax: 714-368-3367
    Email: info@lpaonline.org
  • Little People UK
    P.O Box 1292
    Peterborough PE2 2NT
    United Kingdom
    Phone: 07925893398
    Email: admin@littlepeopleuk.org
  • Short Statured People of Australia
    Australia
    Email: sspaenquiry@gmail.com
  • International Skeletal Dysplasia Registry
    UCLA
    615 Charles E. Young Drive
    South Room 410
    Los Angeles CA 90095-7358
    Phone: 310-825-8998
    Email: AZargaryan@mednet.ucla.edu
  • Skeletal Dysplasia Management Consortium
  • Skeletal Dysplasia Network, European (ESDN)
    Institute of Genetic Medicine
    Newcastle University, International Centre for Life
    Central Parkway
    Newcastle upon Tyne NE1 3BZ
    United Kingdom
    Email: info@esdn.org

References

Literature Cited

  • Acke FR, Dhooge IJ, Malfait F, De Leenheer EM. Hearing impairment in Stickler syndrome: a systematic review. Orphanet J Rare Dis. 2012;7:84. [PMC free article: PMC3551705] [PubMed: 23110709]
  • Barat-Houari M, Baujat G, Tran Mau Them F, Fabre A, Geneviève D, Touitou I. Confirmation of autosomal recessive inheritance of COL2A1 mutations in spondyloepiphyseal dysplasia congenita: lessons for genetic counseling. Am J Med Genet A. 2016a;170A:263–5. [PubMed: 26358419]
  • Barat-Houari M, Dumont B, Fabre A, Them FT, Alembik Y, Alessandri JL, Amiel J, Audebert S, Baumann-Morel C, Blanchet P, Bieth E, Brechard M, Busa T, Calvas P, Capri Y, Cartault F, Chassaing N, Ciorca V, Coubes C, David A, Delezoide AL, Dupin-Deguine D, El Chehadeh S, Faivre L, Giuliano F, Goldenberg A, Isidor B, Jacquemont ML, Julia S, Kaplan J, Lacombe D, Lebrun M, Marlin S, Martin-Coignard D, Martinovic J, Masurel A, Melki J, Mozelle-Nivoix M, Nguyen K, Odent S, Philip N, Pinson L, Plessis G, Quélin C, Shaeffer E, Sigaudy S, Thauvin C, Till M, Touraine R, Vigneron J, Baujat G, Cormier-Daire V, Le Merrer M, Geneviève D, Touitou I. The expanding spectrum of COL2A1 gene variants in 136 patients with a skeletal dysplasia phenotype. Eur J Hum Genet. 2016b;24:992–1000. [PMC free article: PMC5070901] [PubMed: 26626311]
  • Barat-Houari M, Sarrabay G, Gatinois V, Fabre A, Dumont B, Genevieve D, Touitou I. Mutation update for COL2A1 gene variants associated with type II collagenopathies. Hum Mutat. 2016c;37:7–15. [PubMed: 26443184]
  • Bell DM, Leung KK, Wheatley SC, Ng LJ, Zhou S, Ling KW, Sham MH, Koopman P, Tam PP, Cheah KS. SOX9 directly regulates the type-II collagen gene. Nat Genet. 1997;16:174–8. [PubMed: 9171829]
  • Bi W, Deng JM, Zhang Z, Behringer RR, de Crombrugghe B. Sox9 is required for cartilage formation. Nat Genet. 1999;22:85–9. [PubMed: 10319868]
  • Bonafe L, Cormier-Daire V, Hall C, Lachman R, Mortier G, Mundlos S, Nishimura G, Sangiorgi L, Savarirayan R, Sillence D, Spranger J, Superti-Furga A, Warman M, Unger S. Nosology and classification of genetic skeletal disorders: 2015 revision. Am J Med Genet A. 2015;167A:2869–92. [PubMed: 26394607]
  • Castori M, Brancati F, Scanderbeg AC, Dallapiccola B. Hypochondrogenesis. Pediatr Radiol. 2006;36:460–1. [PubMed: 16432703]
  • Hoornaert KP, Dewinter C, Vereecke I, Beemer FA, Courtens W, Fryer A, Fryssira H, Lees M, Müllner-Eidenböck A, Rimoin DL, Siderius L, Superti-Furga A, Temple K, Willems PJ, Zankl A, Zweier C, De Paepe A, Coucke P, Mortier GR. The phenotypic spectrum in patients with arginine to cysteine mutations in the COL2A1 gene. J Med Genet. 2006;43:406–13. [PMC free article: PMC2564515] [PubMed: 16155195]
  • Hoornaert KP, Marik I, Kozlowski K, Cole T, Le Merrer M, Leroy JG, Coucke PJ, Sillence D, Mortier GR. Czech dysplasia metatarsal type: another type II collagen disorder. Eur J Hum Genet. 2007;15:1269–75. [PubMed: 17726487]
  • Kannu P, Bateman J, Savarirayan R. Clinical phenotypes associated with type II collagen mutations. J Paediatr Child Health. 2012;48:E38–43. [PubMed: 21332586]
  • Kannu P, Bateman JF, Randle S, Cowie S, du Sart D, McGrath S, Edwards M, Savarirayan R. Premature arthritis is a distinct type II collagen phenotype. Arthritis Rheum. 2010;62:1421–30. [PubMed: 20131279]
  • Kannu P, Irving M, Aftimos S, Savarirayan R. Two novel COL2A1 mutations associated with a Legg-Calve-Perthes disease-like presentation. Clin Orthop Relat Res. 2011;469:1785–90. [PMC free article: PMC3094608] [PubMed: 21442341]
  • Kozlowski K, Marik I, Marikova O, Zemkova D, Kuklik M. Czech dysplasia metatarsal type. Am J Med Genet A. 2004;129A:87–91. [PubMed: 15266623]
  • Liberfarb RM, Levy HP, Rose PS, Wilkin DJ, Davis J, Balog JZ, Griffith AJ, Szymko-Bennett YM, Johnston JJ, Francomano CA, Tsilou E, Rubin BI. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med. 2003;5:21–7. [PubMed: 12544472]
  • Marik I, Marikova O, Zemkova D, Kuklik M, Kozlowski K. Dominantly inherited progressive pseudorheumatoid dysplasia with hypoplastic toes. Skeletal Radiol. 2004;33:157–64. [PubMed: 14730409]
  • Nagendran S, Richards AJ, McNinch A, Sandford RN, Snead MP. Somatic mosaicism and the phenotypic expression of COL2A1 mutations. Am J Med Genet A. 2012;158A:1204–7. [PubMed: 22496037]
  • Nakashima Y, Sakamoto Y, Nishimura G, Ikegawa S, Iwamoto Y. A novel type II collagen gene mutation in a family with spondyloepiphyseal dysplasia and extensive intrafamilial phenotypic diversity. Hum Genome Var. 2016;3:16007. [PMC free article: PMC4871930] [PubMed: 27274858]
  • Nishimura G, Haga N, Kitoh H, Tanaka Y, Sonoda T, Kitamura M, Shirahama S, Itoh T, Nakashima E, Ohashi H, Ikegawa S. The phenotypic spectrum of COL2A1 mutations. Hum Mutat. 2005;26:36–43. [PubMed: 15895462]
  • Nishimura G, Nakashima E, Mabuchi A, Shimamoto K, Shimamoto T, Shimao Y, Nagai T, Yamaguchi T, Kosaki R, Ohashi H, Makita Y, Ikegawa S. Identification of COL2A1 mutations in platyspondylic skeletal dysplasia, Torrance type. J Med Genet. 2004;41:75–9. [PMC free article: PMC1757240] [PubMed: 14729840]
  • Okamoto T, Nagaya K, Asai H, Tsuchida E, Nohara F, Hayashi T, Yamashita A, Nishimura G, Azuma H. Platyspondylic lethal dysplasia torrance type with a heterozygous mutation in the triple helical domain of COL2A1 in two sibs from phenotypically normal parents. Am J Med Genet A. 2012;158A:1953–6. [PubMed: 22711552]
  • Pacella E, Malvasi A, Tinelli A, Laterza F, Dell'Edera D, Pacella F, Mazzeo F, Ferraresi A, Malarska KG, Cavallotti C. Stickler syndrome in Pierre-Robin sequence prenatal ultrasonographic diagnosis and postnatal therapy: two cases report. Eur Rev Med Pharmacol Sci. 2010;14:1051–4. [PubMed: 21375138]
  • Richards AJ, Laidlaw M, Whittaker J, Treacy B, Rai H, Bearcroft P, Baguley DM, Poulson A, Ang A, Scott JD, Snead MP. High efficiency of mutation detection in type 1 stickler syndrome using a two-stage approach: vitreoretinal assessment coupled with exon sequencing for screening COL2A1. Hum Mutat. 2006;27:696–704. [PubMed: 16752401]
  • Rose PS, Ahn NU, Levy HP, Magid D, Davis J, Liberfarb RM, Sponseller PD, Francomano CA. The hip in Stickler syndrome. J Pediatr Orthop. 2001;21:657–63. [PubMed: 11521037]
  • Rose PS, Levy HP, Liberfarb RM, Davis J, Szymko-Bennett Y, Rubin BI, Tsilou E, Griffith AJ, Francomano CA. Stickler syndrome: clinical characteristics and diagnostic criteria. Am J Med Genet A. 2005;138A:199–207. [PubMed: 16152640]
  • Savarirayan R, Bompadre V, Bober MB, Cho TJ, Goldberg MJ, Hoover-Fong J, Irving M, Kamps SE, Mackenzie WG, Raggio C, Spencer SS, White KK, et al. Best practice guidelines regarding diagnosis and management of patients with type II collagen disorders. Genet Med. 2019. Epub ahead of print. [PubMed: 30696995]
  • Savarirayan R, Rossiter JP, Hoover-Fong JE, Irving M, Bompadre V, Goldberg MJ, Bober MB, Cho TJ, Kamps SE, Mackenzie WG, Raggio C, Spencer SS, White KK, et al. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia. Am J Obstet Gynecol. 2018;219:545–62. [PubMed: 30048634]
  • Sergouniotis PI, Fincham GS, McNinch AM, Spickett C, Poulson AV, Richards AJ, Snead MP. Ophthalmic and molecular genetic findings in Kniest dysplasia. Eye (Lond). 2015;29:475–82. [PMC free article: PMC4816360] [PubMed: 25592122]
  • Snead MP, McNinch AM, Poulson AV, Bearcroft P, Silverman B, Gomersall P, Parfect V, Richards AJ. Stickler syndrome, ocular-only variants and a key diagnostic role for the ophthalmologist. Eye (Lond). 2011;25:1389–400. [PMC free article: PMC3213659] [PubMed: 21921955]
  • Soulier M, Sigaudy S, Chau C, Philip N. Prenatal diagnosis of Pierre-Robin sequence as part of Stickler syndrome. Prenat Diagn. 2002;22:567–8. [PubMed: 12124689]
  • Spranger JW, Brill PW, Nishimura G, Superti-Furga A, Unger S. Type 2 collagen group. In: Spranger JW, Brill P, Superti-Furga A, Unger S, Nishimura G, eds. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 3 ed. New York: Oxford University Press. 2012a.
  • Spranger JW, Brill PW, Nishimura G, Superti-Furga A, Unger S. Type 2 collagen group: achondrogenesis type 2. In: Spranger JW, Brill P, Superti-Furga A, Unger S, Nishimura G, eds. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 3 ed. New York: Oxford University Press. 2012b.
  • Spranger JW, Brill PW, Nishimura G, Superti-Furga A, Unger S. Type 2 collagen group: Kniest dysplasia. In: Spranger JW, Brill P, Superti-Furga A, Unger S, Nishimura G, eds. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 3 ed. New York: Oxford University Press. 2012c.
  • Spranger JW, Brill PW, Nishimura G, Superti-Furga A, Unger S. Type 2 collagen group: spondyloepiphyseal dysplasia. In: Spranger JW, Brill P, Superti-Furga A, Unger S, Nishimura G, eds. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 3 ed. New York: Oxford University Press. 2012d.
  • Spranger JW, Brill PW, Nishimura G, Superti-Furga A, Unger S. Type 2 collagen group: spondyloepiphyseal dysplasia Torrance type. In: Spranger JW, Brill P, Superti-Furga A, Unger S, Nishimura G, eds. Bone Dysplasias: An Atlas of Genetic Disorders of Skeletal Development. 3 ed. New York: Oxford University Press. 2012e.
  • Stevenson DA, Vanzo R, Damjanovich K, Hanson H, Muntz H, Hoffman RO, Bayrak-Toydemir P. Mosaicism in Stickler syndrome. Eur J Med Genet. 2012;55:418–22. [PMC free article: PMC3674818] [PubMed: 22522174]
  • Su P, Li R, Liu S, Zhou Y, Wang X, Patil N, Mow CS, Mason JC, Huang D, Wang Y. Age at onset-dependent presentations of premature hip osteoarthritis, avascular necrosis of the femoral head, or Legg-Calve-Perthes disease in a single family, consequent upon a p.Gly1170Ser mutation of COL2A1. Arthritis Rheum. 2008;58:1701–6. [PubMed: 18512791]
  • Szymko-Bennett YM, Mastroianni MA, Shotland LI, Davis J, Ondrey FG, Balog JZ, Rudy SF, McCullagh L, Levy HP, Liberfarb RM, Francomano CA, Griffith AJ. Auditory dysfunction in Stickler syndrome. Arch Otolaryngol Head Neck Surg. 2001;127:1061–8. [PubMed: 11556853]
  • Terhal PA, Nievelstein RJ, Verver EJ, Topsakal V, van Dommelen P, Hoornaert K, Le Merrer M, Zankl A, Simon ME, Smithson SF, Marcelis C, Kerr B, Clayton-Smith J, Kinning E, Mansour S, Elmslie F, Goodwin L, van der Hout AH, Veenstra-Knol HE, Herkert JC, Lund AM, Hennekam RC, Mégarbané A, Lees MM, Wilson LC, Male A, Hurst J, Alanay Y, Annerén G, Betz RC, Bongers EM, Cormier-Daire V, Dieux A, David A, Elting MW, van den Ende J, Green A, van Hagen JM, Hertel NT, Holder-Espinasse M, den Hollander N, Homfray T, Hove HD, Price S, Raas-Rothschild A, Rohrbach M, Schroeter B, Suri M, Thompson EM, Tobias ES, Toutain A, Vreeburg M, Wakeling E, Knoers NV, Coucke P, Mortier GR. A study of the clinical and radiological features in a cohort of 93 patients with a COL2A1 mutation causing spondyloepiphyseal dysplasia congenita or a related phenotype. Am J Med Genet A. 2015;167A:461–75. [PubMed: 25604898]
  • Tham E, Nishimura G, Geiberger S, Horemuzova E, Nilsson D, Lindstrand A, Hammarsjö A, Armenio M, Mäkitie O, Zabel B, Nordgren A, Nordenskjöld M, Grigelioniene G. Autosomal recessive mutations in the COL2A1 gene cause severe spondyloepiphyseal dysplasia. Clin Genet. 2015;87:496–8. [PubMed: 25060605]
  • Walter K, Tansek M, Tobias ES, Ikegawa S, Coucke P, Hyland J, Mortier G, Iwaya T, Nishimura G, Superti-Furga A, Unger S. COL2A1-related skeletal dysplasias with predominant metaphyseal involvement. Am J Med Genet A. 2007;143A:161–7. [PubMed: 17163530]
  • White KK, Bompadre V, Goldberg MJ, Bober MB, Cho TJ, Hoover-Fong JE, Irving M, Mackenzie WG, Kamps SE, Raggio C, Redding GJ, Spencer SS, Savarirayan R, Theroux MC, et al. Best practices in peri-operative management of patients with skeletal dysplasias. Am J Med Genet A. 2017;173:2584–95. [PubMed: 28763154]
  • Yasuda H, Oh CD, Chen D, de Crombrugghe B, Kim JH. A novel regulatory mechanism of type II collagen expression via a SOX9-dependent enhancer in intron 6. J Biol Chem. 2017;292:528–38. [PMC free article: PMC5241729] [PubMed: 27881681]
  • Yazici Z, Kline-Fath BM, Laor T, Tinkle BT. Fetal MR imaging of Kniest dysplasia. Pediatr Radiol. 2010;40:348–52. [PubMed: 20020120]
  • Zankl A, Zabel B, Hilbert K, Wildhardt G, Cuenot S, Xavier B, Ha-Vinh R, Bonafé L, Spranger J, Superti-Furga A. Spondyloperipheral dysplasia is caused by truncating mutations in the C-propeptide of COL2A1. Am J Med Genet A. 2004;129A:144–8. [PubMed: 15316962]

Acknowledgments

Dr Supriya Raj for helping with the tables, references, and proofreading.

Revision History

  • 25 April 2019 (sw) Review posted live
  • 22 January 2019 (rs) Original submission
Copyright © 1993-2019, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.

GeneReviews® chapters are owned by the University of Washington. Permission is hereby granted to reproduce, distribute, and translate copies of content materials for noncommercial research purposes only, provided that (i) credit for source (http://www.genereviews.org/) and copyright (© 1993-2019 University of Washington) are included with each copy; (ii) a link to the original material is provided whenever the material is published elsewhere on the Web; and (iii) reproducers, distributors, and/or translators comply with the GeneReviews® Copyright Notice and Usage Disclaimer. No further modifications are allowed. For clarity, excerpts of GeneReviews chapters for use in lab reports and clinic notes are a permitted use.

For more information, see the GeneReviews® Copyright Notice and Usage Disclaimer.

For questions regarding permissions or whether a specified use is allowed, contact: ude.wu@tssamda.

Bookshelf ID: NBK540447PMID: 31021589

Views

Tests in GTR by Gene

Related information

  • PMC
    PubMed Central citations
  • PubMed
    Links to PubMed

Similar articles in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...