Type Ii Collagen Disorders Overview

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2021-01-18

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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.

Diagnosis

Clinical Characteristics

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 Disorder	Gene(s)	MOI	Clinical Features of Differential Diagnosis Disorder
Type II Collagen Disorder	Differential Diagnosis Disorder	Gene(s)	MOI	Overlapping w/type II collagen disorders	Distinguishing 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
	Hypophosphatasia	ALPL	AD 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)	TRIP11	AR	Poor/delayed ossification Hydropic appearance	Poorly ossified skull bones Short, thin, easily fractured ribs Tubular bones more severely shortened & bowed
	Achondrogenesis type 1B	SLC26A2	AR	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 2	SLC26A2	AR	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 dysplasia	SLC26A2	AR	Short limbs Spine & joint deformities	Hitchhiker thumbs/toes
	Dyssegmental dysplasia, Silverman-Handmaker type (OMIM 224410) (may include Rolland-Desbuquois type)	HSPG2	AR	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	TRPV4	AD	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, AD	COL9A1 COL9A2 COL9A3 COMP MATN3	AD	Presents in early childhood, usually w/pain in hips &/or knees	No facial, ophthalmic, or auditory abnormalities ² Often no spine involvement
	MED, recessive	SLC26A2	AR	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)	CCN6	AR	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, & 5	COL11A1 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 Disorder	Differential Diagnosis Disorder	Clinical Features of Differential Diagnosis Disorder
Type II Collagen Disorder	Differential Diagnosis Disorder	Overlapping w/type II collagen disorders	Distinguishing from type II collagen disorders
Intermediate severity – spondyloperipheral dysplasia; SED w/metatarsal shortening (Czech dysplasia) ¹; Stickler syndrome type 1	Juvenile idiopathic arthritis	Presents in childhood, usually w/joint pain	No facial, ophthalmic, or auditory abnormalities ³
	Calve-Legg Perthes ²	Presents 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
Mild severity – mild SED w/premature arthrosis	Juvenile idiopathic arthritis	Joint 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)

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/Concern	Evaluation	Comment
Skeleton	Complete 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 spine	Clinical examination & radiographs where indicated	Evaluate 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
Eyes	Dilated eye examination	Preferably 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
Feeding	Swallowing assessment	In 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.
Genetics	Consultation 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

: Adapted from Savarirayan et al [2019]
: PRS = Pierre Robin sequence

Treatment of Manifestations

Table 4.

Treatment of Manifestations in Individuals with Type II Collagen Disorders

Manifestation/ Concern	Treatment	Considerations/Other
Cervical spine instability w/spine compression	Surgical management for medullopathy (C1-C2 fixation)	Management by an expert familiar w/rare skeletal dysplasia & spine involvement
Scoliosis	Surgery for severe, progressive scoliosis	In 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 palate	Surgery
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 impairment	Hearing 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
Obesity	Referral to clinical nutritionist	Even if weight is normal, importance of avoiding obesity should be emphasized.
Psychosocial problems	Referral to resources Referral to psychologist

: Adapted from Savarirayan et al [2019]
: CPAP = continuous positive airway pressure

Surveillance

Table 5.

Recommended Surveillance for Individuals with Type II Collagen Disorders

System/ Concern	Evaluation	Frequency
General health	Physical examination	Annually 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
Eyes	Dilated 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
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